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Thèses sur le sujet « Tyrosine Kinase Inhibitors (TKIs) »

Auteur : Grafiati
Publié le 9 mars 2023
Mis à jour le 10 mars 2023

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1

Recondo, Gonzalo. « Resistance Mechanisms to ALK Tyrosine Kinase Inhibitors (TKIs) in NSCLC ». Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS248/document.

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Les analyses moléculaires et la classification des adénocarcinomes bronchiques ont conduit au développement de thérapies ciblées sélectives visant à améliorer le contrôle de la maladie et la survie des patients. ALK (anaplastic lymphoma kinase) est un récepteur tyrosine kinase de la famille des récepteurs de l'insuline. Des réarrangements chromosomiques impliquant le domaine kinase d’ALK sont présents dans environ 3 à 6% des patients atteints d'un adénocarcinome bronchique. La protéine de fusion provoque une activation du domaine kinase de manière constitutive et indépendante du ligand. Lorlatinib est un inhibiteur d’ALK de troisième génération avec une efficacité et une sélectivité optimale, ainsi qu’une pénétration élevée vers le système nerveux central. Lorlatinib peut vaincre la résistance induite par plus de 16 mutations secondaires dans le domaine kinase d’ALK acquises lors de la progression aux ALK TKI de première et deuxième générations. Le traitement par lorlatinib est donc efficace chez les patients préalablement traités par un ALK TKI de première ou deuxième génération, et est actuellement approuvé pour cette indication. Le spectre complet de mécanismes de résistance au lorlatinib chez les patients reste à élucider. Il a récemment été rapporté que l'acquisition séquentielle de deux mutations ou plus dans le domaine kinase, également appelées mutations composées, est responsable de la progression de la maladie chez environ 35% des patients traités par le lorlatinib, principalement en altérant sa liaison au domaine kinase d’ALK. Cependant, l’effet de ces mutations sur la sensibilité aux différents inhibiteurs d’ALK peut varier, et les autres mécanismes de résistance survenant chez la plupart des patients restent inconnus. Mon travail de thèse avait pour but d’explorer la résistance au lorlatinib chez des patients atteints d'un cancer du poumon ALK réarrangé par la mise en œuvre de biopsies spatiales et temporelles et le développement de modèles dérivés de patients. Dans le cadre de l’étude institutionnelle MATCH-R (NCT02517892), nous avons effectué un séquençage à haut débit de l’exome, de l’ARN et ciblé, ainsi qu’un séquençage des ctDNA afin d’identifier les mécanismes de résistance. Nous avons établi des lignées cellulaires dérivées de patients et caractérisé de nouveaux mécanismes de résistance et identifiés de nouvelles stratégies thérapeutiques in vitro et in vivo. Nous avons identifié trois mécanismes de résistance chez quatre patients avec des biopsies appariées. Nous avons étudié l'induction de la transition épithélio-mésenchymateuse (EMT) par l'activation de SRC dans une lignée cellulaire, dérivée d’un patient, exposée au lorlatinib. Les cellules mésenchymateuses étaient sensibles à l’inhibition combinée de SRC et d'ALK, montrant que même en présence d'un phénotype agressif, des stratégies de combinaison peuvent surmonter la résistance aux ALK TKI. Nous avons identifié deux nouvelles mutations composées du domaine kinase d’ALK, F1174L / G1202R, C1156Y / G1269A survenues chez deux patients traités par le lorlatinib. Nous avons développé des modèles de cellules Ba / F3 exprimant les mutations simples et composées pour étudier leur effet sur la résistance au lorlatinib. Enfin, nous avons caractérisé un nouveau mécanisme de résistance provoqué par la perte de fonction de NF2 au moment de la progression du lorlatinib par l’utilisation de PDX et de lignées cellulaires dérivées de patients, et par CRISPR / CAS9 knock-out de NF2. Nous avons constaté que l'activation de mTOR par la perte de fonction de NF2 provoquait la résistance au lorlatinib et qu'elle pouvait être surmontée par le traitement avec des inhibiteurs de mTOR.Cette étude montre que les mécanismes de résistance au lorlatinib sont plus divers et complexes que prévu. Nos résultats démontrent également comment les études longitudinales de la dynamique tumorale permettent de déchiffrer la résistance aux TKI et d'identifier des stratégies thérapeutiques
The molecular study and classification of lung adenocarcinomas has led to the development of selective targeted therapies aiming to improve disease control and survival in patients. The anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor from the insulin tyrosine kinase receptor family, with a physiologic role in neural development. Gene rearrangements involving the ALK kinase domain occur in ~3-6% of patients with lung adenocarcinoma. The fusion protein dimerizes leading to transactivation of the ALK kinase domain in a ligand-independent and constitutive manner. Lorlatinib is a third generation ALK inhibitor with high potency and selectivity for this kinase in vitro and in vivo, and elevated penetrance in the central nervous system. Lorlatinib can overcome resistance mediated by over 16 secondary kinase domain mutations occurring in 13 residues upon progression to first - and second - generation ALK TKI. In addition, treatment with lorlatinib is effective for patients who have been previously treated with a first and a second generation or a second generation ALK TKI upfront and is currently approved for this indication. The full spectrum of biological mechanisms driving lorlatinib resistance in patients remains to be elucidated. It has been recently reported that the sequential acquisition of two or more mutations in the kinase domain, also referred as compound mutations, is responsible for disease progression in about 35% of patients treated with lorlatinib, mainly by impairing its binding to the ALK kinase domain. However, the effect of these compound mutations on the sensitivity to the repertoire of ALK inhibitors can vary, and other resistance mechanisms occurring in most patients are unknown. My PhD thesis aimed at exploring resistance to lorlatinib in patients with ALK-rearranged lung cancer through spatial and temporal tumor biopsies and development of patient-derived models. Within the institutional MATCH-R study (NCT02517892), we performed high-throughput whole exome, RNA and targeted next-generation sequencing, together with plasma sequencing to identify putative genomic and bypass mechanisms of resistance. We developed patient-derived cell lines and characterized novel mechanisms of resistance and personalized treatment strategies in vitro and in vivo. We characterized three mechanisms of resistance in four patients with paired biopsies. We studied the induction of epithelial-mesenchymal transition (EMT) by SRC activation in a patient-derived cell line exposed to lorlatinib. Mesenchymal cells were sensitive to combined SRC and ALK co-inhibition, showing that even in the presence of an aggressive and challenging phenotype, combination strategies can overcome ALK resistance. We identified two novel ALK kinase domain compound mutations, F1174L/G1202R, C1156Y/G1269A, occurring in two patients treated with lorlatinib. We developed Ba/F3 cell models harboring single and compound mutations to study the differential effect of these mutations on lorlatinib resistance. Finally, we characterized a novel mechanism of resistance caused by NF2 loss of function at the time of lorlatinib progression through the development of patients derived PDX and cell lines, and in vitro validation of NF2 knock-out with CRISPR/CAS9 gene editing. Downstream activation of mTOR was found to drive lorlatinib resistance by NF2 loss of function and was overcome by providing treatment with mTOR inhibitors.This study shows that mechanisms of resistance to lorlatinib are more diverse and complex than anticipated. Our findings also emphasize how longitudinal studies of tumor dynamics allow deciphering TKI resistance and identifying reversing strategies
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2

SARONNI, DAVIDE. « TYROSINE KINASE INHIBITORS IN NEUROENDOCRINE TUMORS : FROM IN VITRO TO ZEBRAFISH MODEL ». Doctoral thesis, Università degli Studi di Milano, 2022. http://hdl.handle.net/2434/917967.

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(1) Background: Neuroendocrine neoplasms (NENs) are a group of tumors that arise from neuroendocrine cells throughout the body, with the lungs and gastrointestinal tract being the most common sites of origin. In patients with NENs and distant metastases, surgery is generally not curative. Although well-differentiated and low-grade NENs, classified as neuroendocrine tumors (NETs), are usually less aggressive than poorly-differentiated NENs, they can develop distant metastases in about 15% of cases. These patients require chronic medical management. However, the clinical efficacy of these treatments is limited by the low objective response rate, due to the occurrence of tumor resistance and the high biological heterogeneity of these neoplasms. (2) Research problem: We addressed this study on two rare NETs: lung neuroendocrine tumors (LNETs) and medullary thyroid carcinoma (MTC). LNETs represent about 2% of lung tumors, while MTCs are rare thyroid tumors caused by mutations in the RET proto-oncogene. Both NETs are well-differentiated neoplasms and are known to be highly vascularized. Therefore, they represent a potential target for tyrosine kinase inhibitors (TKIs) selective for receptors involved in angiogenesis. The aim of this project was to evaluate the antitumor activity of several new TKIs both in vitro, using LNETs (NCI-H727, UMC-11 and NCI-H835) and MTC (TT and MZ-CRC-1) cell lines, and in vivo, adopting a novel zebrafish xenograft model to study angiogenesis. In LNETs we tested: sulfatinib, a small molecule that inhibits the Vascular Endothelial Growth Factor Receptor (VEGFR) 1, 2, and 3, and the Fibroblast Growth Factor Receptor type 1 (FGFR1); cabozantinib, a multi-target inhibitor selective for VEGFR2, c-Met, Kit, Axl and Flt3; and axitinib, a multi-target TKI of VEGFR1, 2, 3 and Platelet-Derived Growth Factor Receptor-beta (PDGFRβ). In MTC we tested: sulfatinib; SPP86, a RET-specific inhibitor; and SU5402, an inhibitor of the FGFR1 and VEGFR2. (3) Methodology: In LNETs and MTC cells the effects of selected TKIs have been evaluated in vitro through: MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assays, for assessing cell viability; flow-cytometer analysis, for the evaluation of cell cycle and apoptosis; and wound-healing assay, to study cell migration. In vivo we took advantage of the transgenic zebrafish line of Tg(fli1a:EGFP)y1. Through the xenotransplantation of NET cells in the subperidermal space near the subintestinal vein, we assessed the effects of TKIs on tumor-induced angiogenesis and cancer dissemination. (4) Key Results: In LNET cell lines we observed a dose-dependent decrease in cell viability after incubation with all TKIs. This effect seems to be related to the perturbation of the cell cycle and induction in apoptosis. In NCI-H727 wound healing assay showed a significant reduction in cell migration only after incubation with cabozantinib. In the zebrafish model, we found a significant reduction of the tumor-induced angiogenesis in implanted LNET cell lines after treatment with all TKIs. Cabozantinib and axitinib were more potent than sulfatinib in inhibition of angiogenesis, while cabozantinib was the most efficient in reducing cell migration from the transplantation site to the tail. In MTC cell lines, sulfatinib, SU5402 and SPP86 showed a decrease in cell viability, confirmed by the significant reduction in S phase cell population. Moreover, sulfatinib and SPP86 showed for both cell lines a significant induction of apoptosis. Sulfatinib and SPP86 inhibited the migration of TT and MZCRC-1 cells, evaluated through the wound healing assay, while SU5402 was able to inhibit migration only in TT cells. In vivo we observed a significant reduction of TT cells-induced angiogenesis in zebrafish embryos after treatment with sulfatinib and SPP86. (5) Conclusions: Despite sulfatinib resulted the most potent compound in terms of inhibition of LNET cell proliferation, cabozantinib showed in vivo the most effective impact in reducing tumor-induced angiogenesis. Cabozantinib was the only TKI able to inhibit in vivo the dissemination of implanted LNET cells. According to these data, cabozantinib could represent a potential candidate in the therapy of patients with highly vascularized LNET. In MTC cell lines, SPP86 and sulfatinib displayed a similar antitumor activity both in vitro and in vivo, suggesting a good efficacy of specific RET inhibitors (SPP86) with potentially less adverse effects than multitarget TKIs (sulfatinib). In addition, this study showed that the zebrafish model for NETs represents an innovative tool for drug screening with several advantages compared with rodent models: rapidity of procedure, animal immune suppression is not required, lower number of tumor cells for implant and the optical transparency provides a real-time monitoring of cell-stromal interactions and cancer progression in living animals.
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DAMELE, LAURA. « Effect of tyrosine kinase inhibitors on NK cell and ILC3 dvelopment and function ». Doctoral thesis, Università degli studi di Genova, 2020. http://hdl.handle.net/11567/996010.

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Tyrosin kinase inhibitors (TKI) sharply improved the prognosis of Chronic Myeloid Leukemia (CML) and of Philadelphia+ Acute Lymphoblastic Leukemia (Ph+ALL) patients. However, TKI are not curative because of the development of resistance and lack of complete molecular remission in the majority of patients. Clinical evidences would support the notion that patient’s immune system may play a key role in preventing relapses. In particular, increased proportions of terminally differentiated CD56+CD16+CD57+ NK cells have been reported to be associated with successful Imatinib therapy discontinuation or with a deep molecular response in Dasatinib-treated patients. In view of the potential role of NK cells in immune-response against CML, it is important to study whether any TKI have an effect on the NK cell development and identify possible molecular mechanism(s) by which continuous exposure to in vitro TKI may influence NK cell development and repertoire. To this end, CD34+ hematopoietic stem cells (HSC) were cultured in the absence or in the presence of Imatinib, Nilotinib, or Dasatinib. We show that all compounds exert an inhibitory effect on CD56+ cell recovery. In addition, Dasatinib sharply skewed the repertoire of CD56+ cell population, leading to an impaired recovery of CD56+CD117−CD16+CD94/NKG2A+EOMES+ mature cytotoxic NK cells, while the recovery of CD56+CD117+CD94/NKG2A−RORgt+ IL-22-producing ILC3 was not affected. This effect appears to involve the Dasatinib–mediated inhibition of Src kinases and, indirectly, of STAT5-signaling activation in CD34+ cells during first days of culture. Our studies, reveal a possible mechanism by which Dasatinib may interfere with the proliferation and maturation of fully competent NK cells, i.e., by targeting signaling pathways required for differentiation and survival of NK cells but not of ILC3.
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Aljohani, Hashim M. B. S. « Signaling Pathways Associated with Gefitinib Resistance in Glioblastoma Multiforme (GBM) ». University of Cincinnati / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1406900804.

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5

Tonus, Francesca. « Sintesi e studio di sistemi polieterociclici a potenziale attività biologica ». Doctoral thesis, Università degli studi di Padova, 2012. http://hdl.handle.net/11577/3425459.

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In the last decade, some progresses have been reached in the cancer treatment, mainly through the approval of novel key drugs based on the targeted therapy. In this respect, tyrosine kinases constitute one of the most relevant class of targets. Tyrosine kinases are key enzymes involved in the intracellular signal transduction and their up-regulation is often associated with cancer onset and progression. The tyrosine kinase inhibitors act mainly as ATP-mimic compounds. Despite the initial relevant clinical successes obtained through kinase inhibitor use, rapid drug resistance phenomena onset have been recently emerged when administering highly selective drugs. Consequently, a major goal in the field of tyrosine kinase inhibitor development is to find compounds able to inhibit more than one enzyme, thus overcoming the drug resistance onset. The synthesis and the biological evaluation of new potential kinase inhibitors are described in this work. Three different quinazoline analogs have been previously identified by our research group, that share the same 3-aminobiphenyl function condensed at 4-position (Figure 1). These compounds were found to posses higher inhibitory potency against cell proliferation when compared with analogues bearing simple aniline moieties condensed at 4-position. Thus, starting from these results, four classes of quinazoline compounds have been synthesized. The designed derivatives are characterized by different substituents condensed on the dioxanoquinazoline nucleus (n=2) or by different side chains at the position 6 and 7 to the quinazoline nucleus. The quinazoline scaffolds have been synthesized according to an innovative and useful strategy developed by our research group 1. All the synthesized compounds have been evaluated for their antiproliferative effects on A431 cells that over-express EGFR. In order to define the mechanism of action of the most active compounds, the irreversibility of the effects on the cell growth as well as the interactions with EGFR have been investigated. The effects on HUVEC proliferation, migration and morphogenesis have also been evaluated to assess the antiangiogenic properties of the derivatives. Finally, the compounds have been tested on a panel of human tumor cell lines and on 7 different purified kinases.
Nell’ultimo decennio sono stati fatti molti progressi nell’ambito della terapia antitumorale, soprattutto grazie allo sviluppo della targeted therapy che ha portato all’approvazione di nuovi importanti farmaci. Tra i target di elezione per la targeted therapy particolare rilevanza hanno le tirosinchinasi. Le tirosinchinasi sono enzimi fondamentali nella trasduzione del segnale intracellulare e quando sovra-espresse, come spesso accade nelle cellule tumorali, portano ad una de-regolazione e ad un’aumentata proliferazione cellulare. I farmaci approvati come inibitori tirosinchinasici sono per lo più molecole ad azione ATP-mimetica. Nonostante l’iniziale entusiasmo derivante dalla loro elevata efficacia terapeutica, oggi si riscontrano sempre più frequentemente fenomeni di resistenza che rendono inefficace la somministrazione di questi farmaci. Per cercare di superare questo problema la ricerca si sta impegnando nella scoperta di farmaci che siano multi-target, ovvero inibitori multi-chinasici. A partire da queste considerazioni il progetto di dottorato è stato dedicato alla sintesi e alla valutazione biologica di nuovi potenziali inibitori tirosinchinasici. Da studi precedentemente effettuati all’interno dei laboratori di ricerca in cui questa tesi è stata svolta, era risultato che la funzionalizzazione con 3-amminobifenile di tre diversi nuclei chinazolinici (figura 1) conferiva una maggior potenza inibitoria nei confronti della proliferazione cellulare rispetto ad altri tipi di sostituenti anilinici. Sono state quindi progettate e sintetizzate quattro classi di composti che differissero per il sostituente in 4 rispetto al nucleo diossanochinazolinico (n=2) o per i sostituenti in 6 o 7 all’anello chinazolinico. I nuclei chinazolinici sono stati tutti ottenuti seguendo una metodica generale di sintesi messa a punto e validata nel nostro gruppo di ricerca 1. Per tutti i composti sintetizzati sono stati valutati gli effetti antiproliferativi sulla linea cellulare A431 che sovra-esprime EGFR 2. Il meccanismo di azione dei composti maggiormente attivi è stato quindi indagato, verificando l’irreversibilità dell’azione e la specificità nei confronti di EGFR. Sono stati valutati anche gli effetti sulla proliferazione, sulla migrazione e sulla morfogenesi di cellule HUVEC allo scopo di indagare l’attività antiangiogenica dei nuovi derivati. Per avere un quadro più completo dell’attività di questi derivati sono stati, infine, valutati gli effetti antiproliferativi su un ampio pannello di linee cellulari tumorali umane e gli effetti inibitori su 7 diverse tirosinchinasi isolate (sia recettoriali che citoplasmatiche).
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Russell, Kathy, Marion Slack, Janet Cooley et Kelly Mathews. « Impact of a Specialty Pharmacy-Based Oral Chemotherapy Adherence Program on Patient Adherence ». The University of Arizona, 2016. http://hdl.handle.net/10150/614015.

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Class of 2016 Abstract
Objectives: Patient medication adherence is a basic requirement for treating chronic myelogenous leukemia (CML) with oral tyrosine kinase inhibitors (TKIs). When imatinib adherence rates are less than 80 or 90 percent, major and complete molecular responses, respectively, do not happen. The purpose of this study was to determine the effect of a real-time medication monitoring (RTMM) reminder system adherence program on the medication possession ratio (MPR). Methods: This analytic study was a retrospective cohort study and used data extracted from chart reviews for patients who received services from 2011 to 2015. It was approved by the Institutional Review Board. The study consisted of an intervention group and a control group (50 patients each). MPRs, demographic, descriptive, and categorical variables were summarized using means, standard deviations (SD), and frequencies/percentages. Results: The study population consisted of adult patients (mean age=62.2, SD=2.7, 50% male) treated by Avella Specialty Pharmacy who received imatinib or nilotinib as treatment for CML, gastrointestinal stromal tumors (GIST), or a similar positive Philadelphia chromosome cancer. Only 4% of patients in the intervention group had an < 85% MPR, compared to 46% in the control group (p < 0.001). Conclusions: In those patients who had an MPR of ≥ 85%, the difference between the groups was statistically significant. As past studies have shown, adherence rates greater than 90% have a higher likelihood of a major or complete molecular response and a greatly reduced risk of disease progression.
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Choi, Ho-ying, et 蔡可盈. « Review of clinical benefits and cost effectiveness of epidermal growthfactor receptor-tyrosine kinase inhibitor (EGFR-TKI) as first linetreatment for patients with advanced non-small cell lung cancer(NSCLC) ». Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B46935320.

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Mazed, Fetta. « Etude des mécanismes de résistance aux inhibiteurs de FLT3 dans les leucémies aigues myéloïdes ». Thesis, Sorbonne Paris Cité, 2019. http://www.theses.fr/2019USPCC089.

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Les leucémies aiguës myéloïdes (LAM) constituent un groupe hétérogène d’hémopathies malignes résultant de la prolifération clonale d’un progéniteur myéloïde bloqué dans sa différenciation. De pronostic globalement défavorable, dépend de l’âge et de facteurs cytogénétiques et moléculaires. La mutation du gène FLT3 de type duplication en tandem du domaine juxta-membranaire (ITD : internal tandem duplication) est détectée dans 30% des échantillons de LAM, corrèle à une fréquence accrue de rechutes et à un pronostic défavorable. La mutation ITD conduit à une activation dérégulée et constitutive de récepteur FLT3, induisant une addiction oncogénique des cellules leucémiques aux voies de signalisation en aval, désignant FLT3 comme cible thérapeutique pertinente dans les LAM. Ainsi, de nombreux inhibiteurs de tyrosine kinase (ITK) ciblant FLT3 ont été développés, certains ayant une efficacité significative en monothérapie et améliorant la survie des patients ayant une mutation FLT3-ITD en association aux traitements conventionnels. Néanmoins, la plupart des patients traités en monothérapie, et une proportion importante de ceux traités en association rechutent en raison de mécanismes de résistance développés par la cellule pour échapper à l’action des ITK. L’étude de ces mécanismes est un enjeu essentiel afin d’améliorer l’efficacité des traitements dans les LAM FLT3-ITD. C’est cette thématique que j’ai souhaité aborder au cours de ma thèse. Nous avons tout d’abord, mis en évidence par des approches transcriptomiques et protéomiques une nouvelle cible de PIM2, la sérine thréonine kinase RSK2, ayant un rôle dans le contrôle de l’apoptose des cellules de LAM. Mes collègues et moi-même avons montré que RSK2 était fortement diminuée suite à l’invalidation de PIM2 par interférence ARN dans une lignée de LAM FLT3-ITD (MOLM-14), tant au niveau ARNm que protéique. Par une technique de sensibilisation à l’apoptose à l’aide de peptides BH3 ainsi que par un inhibiteur de Bcl-2, le composé ABT-199, nous avons montré le rôle de RSK2 dans le contrôle de l’apoptose mitochondriale en contexte FLT3-ITD. Nous avons ensuite observé que la surexpression de RSK2 compensait la mort cellulaire induite par l’invalidation de PIM2, renforçant ainsi le rôle de cette nouvelle voie dans le contrôle de la survie cellulaire. Finalement, nous avons suggéré dans des modèles murins de la maladie que RSK2 pourrait participer à la résistance aux ITK ciblant FLT3. Afin de poser la question de ces mécanismes de résistance sans à priori, j’ai adapté à notre modèle de LAM une banque CRISPR pan-génomique dans le but de la cribler avec différents ITK et mettre à jour de nouveaux mécanismes de résistance aux ITK. J’ai utilisé l’enzyme dCas9 permettant non pas des cassures de l’ADN mais une modulation de la transcription de gènes cibles, soit une répression lors de la fusion au corépresseur KRAB (CRISPRi), soit une activation lors de la fusion à VP64 (CRISPRa). La dCas9 et les banques ont été transduites par des lentivirus dans 2 lignées FLT3-ITD (MOLM-14 et MV4-11). Ces cellules ont été amplifiées en culture liquide ou sur des cellules stromales mésenchymateuses (MSC) et traitées soit par du DMSO soit par l’un des 3 ITK ciblant FLT3 suivants : quizartinib, midostaurine ou ponatinib. L’identification et la quantification des ARN guides par séquençage haut débit et l’analyse bioinformatique nous renseigne enfin sur les gènes dont la répression favorise l’effet des ITK, pouvant ainsi représenter de nouveaux mécanismes de résistance intrinsèques (culture liquide) et/ou extrinsèques (co-culture MSCs) à la cellule. Le troisième axe de mon travail a porté sur la caractérisation des modifications du profil de signalisation global induites par les mutations du domaine tyrosine kinase (TKD) de FLT3-ITD impliquées dans la résistance aux ITK
Acute myeloid leukemia (AML) is a heterogeneous group of hematological malignancies resulting from the clonal proliferation of a myeloid progenitor blocked in its differentiation. The prognosis of AML is generally unfavorable, depending on age, cytogenetic and molecular factors. The FLT3-ITD mutation, (internal tandem duplication) is detected in 30% of AML patients and correlates with an increased frequency of relapses and an unfavorable prognosis. FLT3-ITD mutations leads to a deregulated and constitutive activation of FLT3 receptors, inducing an oncogenic addiction of leukemic blasts to FLT3-dependent signaling pathways, pinpointing FLT3 as a relevant therapeutic target in AML. Thus, many tyrosine kinase inhibitors (TKI) targeting FLT3 have been developed, some of which harboring significant efficacy in monotherapy and even improving patients’ survival when combined with conventional treatments. However, most patients treated by TKI monotherapy, and a significant proportion of those treated with combined approaches will relapse, due to various escape mechanisms. To study these mechanisms is therefore a major goal to improve the efficacy of treatments in FLT3-ITD LAM which I undertook during my thesis. First, I built on my team’s previous work to discover a new target of PIM2, the RSK2 serine threonine kinase, using transcriptomic and proteomic approaches. We showed that RSK2 expression was greatly decreased following the invalidation of PIM2 by RNA interference in a FLT3-ITD AML line (MOLM-14), both at the mRNA and protein levels. By BH3 profiling, we connected RSK2 to the control of mitochondrial apoptosis in the context of FLT3-ITD cells. We then observed that RSK2 overexpression compensated apoptosis induced by PIM2 knockdown, thus reinforcing the role of this new PIM2/RSK2 pathway in the control of cell survival. Finally, we suggested that RSK2 may be involved in TKI resistance in mouse models of AML. To address the question of FLT3-ITD resistance mechanisms more broadly, I adapted a CRISPR/dCas genome wide library on our AML model, with the purpose of screening it with different TKI to unravel new mechanisms of resistance to these compounds. I used the dCas9 enzyme, devoid of endonuclease activity but modulating target genes expression; inhibition in case of dCas9/KRAB fusion (CRISPRi), or activation in dCas9/VP64 fusion (CRISPRa). Both dCas9 and libraries were transduced by lentiviruses in two FLT3-ITD cell lines (MOLM-14 and MV4-11), grown in liquid culture or on a mesenchymal stromal cells (MSC) layer, and treated either with DMSO or with one of the 3 following ITKs: quizartinib, midostaurine or ponatinib. The identification and quantification of RNAs guides by high-throughput sequencing and bioinformatic identify potential new mechanisms of intrinsic resistance (liquid culture) and / or extrinsic (co-culture MSCs) to TKI. The third area of my work focused on the characterization of global signaling changes induced by FLT3-ITD tyrosine kinase domain (TKD) mutations associated with TKI resistance
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Glauche, Ingmar, Matthias Kuhn, Christoph Baldow, Philipp Schulze, Tino Rothe, Hendrik Liebscher, Amit Roy, Xiaoning Wang et Ingo Roeder. « Quantitative prediction of long-term molecular response in TKI-treated CML – Lessons from an imatinib versus dasatinib comparison ». Macmillan Publishers Limited, part of Springer Nature, 2018. https://tud.qucosa.de/id/qucosa%3A32495.

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Longitudinal monitoring of BCR-ABL transcript levels in peripheral blood of CML patients treated with tyrosine kinase inhibitors (TKI) revealed a typical biphasic response. Although second generation TKIs like dasatinib proved more efficient in achieving molecular remission compared to first generation TKI imatinib, it is unclear how individual responses differ between the drugs and whether mechanisms of drug action can be deduced from the dynamic data. We use time courses from the DASISION trial to address statistical differences in the dynamic response between first line imatinib vs. dasatinib treatment cohorts and we analyze differences between the cohorts by fitting an established mathematical model of functional CML treatment to individual time courses. On average, dasatinib-treated patients show a steeper initial response, while the long-term response only marginally differed between the treatments. Supplementing each patient time course with a corresponding confidence region, we illustrate the consequences of the uncertainty estimate for the underlying mechanisms of CML remission. Our model suggests that the observed BCR-ABL dynamics may result from different, underlying stem cell dynamics. These results illustrate that the perception and description of CML treatment response as a dynamic process on the level of individual patients is a prerequisite for reliable patient-specific response predictions and treatment optimizations.
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Sørum, Christopher. « Synthesis of new tyrosine kinase inhibitors ». Thesis, Norges teknisk-naturvitenskapelige universitet, Institutt for kjemi, 2009. http://urn.kb.se/resolve?urn=urn:nbn:no:ntnu:diva-6863.

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Sahin, Katherine B. « Evaluation of cell division cycle associated protein 3 (CDCA3) as a novel prognostic/therapeutic target for EGFR-mutant non-small cell lung cancer ». Thesis, Queensland University of Technology, 2022. https://eprints.qut.edu.au/231468/1/Katherine_Sahin_Thesis.pdf.

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This thesis defined a unique role for the protein cell division cycle associated protein-3 (CDCA3) in epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC). This thesis has established an association between the levels of CDCA3 expression and the tumour response to tyrosine kinase inhibitors (TKI), which are the front-line therapy for EGFR-mutant NSCLC. In this disease, CDCA3 functions to modulate cellular growth pathways to impact sensitivity towards TKI therapy. Future work might enable development of a clinical stratification tool to discern TKI responsive from non-responsive EGFR-mutant NSCLC tumours.
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Rothe, Tino. « Anwendung mathematischer Modelle zur Vorhersage des Therapieverlaufs von CML-Patienten ». Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2018. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-231508.

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Hintergrund Die chronische myeloische Leukämie (CML) ist eine myeloproliferative Er- krankung, die aufgrund ihres Modellcharakters unter der Behandlung mit Tyrosin-Kinase- Inhibitoren (TKI) gut für eine Beschreibung mittels computerbasierter Modelle geeignet ist. Grundlage für die Entstehung einer CML ist die Bildung eines Philadelphia-Chromosoms durch eine Translokation der Chromosomen 9 und 22. Es resultiert das Onkogen BCR- ABL1, welches für eine konstitutiv aktive Tyrosinkinase codiert. Diese führt zu ungeregelter Proliferation der betroffen Zellen und zur Verdrängung der gesunden Blutbildung. Das überaktivierte Protein kann durch TKIs gezielt gehemmt werden. Damit ist es möglich, die Tumorlast erheblich zu senken und das Fortschreiten der Erkrankung aufzuhalten. Aktuell werden in der klinischen Anwendung außerhalb von Studien TKIs für die gesamte Lebensdauer der Patienten eingesetzt. Absetzstudien zeigten, dass circa 50% der Patienten nach einer über zwei Jahren nicht nachweisbaren BCR-ABL1-Last nach Behandlungsstopp kein erneutes Anwachsen der Tumorlast aufwiesen. Die Anwendung von computergestützten Modellsimulationen hilft, Zugriff auf die klinisch nur schwer zu messenden leukämischen Stammzellen zu bekommen und darüber Vorhersagen über den weiteren Therapieverlauf zu treffen. Aufgabenstellung Im Rahmen der vorliegenden Arbeit sollen Möglichkeiten der Übertragung von Patientendaten auf das etablierte Modell nach Roeder und Loeffler (2002) verbessert werden. Die vom Modell vorhergesagten Stammzellkinetiken sollen abschließend auf Praxistauglichkeit geprüft werden. Material und Methoden Aufgrund der Vergleichbarkeit zu früheren Untersuchungen erfolgte die Auswahl von 51 Patienten des deutsches Armes der IRIS-Studie. Deren Therapieverläufe wurden analysiert und können über eine biphasische exponentielle (biexponentielle) bzw. über eine stückweise lineare Funktion beschreiben werden. Als Erweiterung der Arbeiten von Horn et al. (2013) wurden alle Parameter der biexponentiellen Funktion in die Entwicklung neuer Methoden einbezogen. Zusätzlich wurde untersucht, ob die Einbeziehung von zensierten Messpunkte die Form der biexponentiellen Funktion verändert. Basierend auf den Therapiedaten der IRIS-Patienten erfolgte die Ermittlung eines Para meterraumes für Eingangsparameter der Modellsimulation (Modellparameter), welcher in 270.400 individuelle Paramterkombinationen unterteilt wurde. Es erfolgten anschließend die Simulation und Auswertung nach der biexponentiellen Beschreibung. Auf Basis dieser erheblich größeren Datengrundlage konnten zwei neue Verfahren der Modellparameteridentifikation für individuelle Patienten entwickelt werden. Einerseits wurde in Anlehnung an die Arbeit von Horn et al. (2013) ein Verfahren unter Nutzung der Regression vorgestellt. Andererseits konnte über den Vergleich der Abstände zwischen simulierten und realen Therapieverläufen eine Suche (lookup-table) etabliert werden. Die Berechnung des Abstandes zwischen Therapieverläufen ermöglicht gleichzeitig den Vergleich der verschiedenen Verfahren und damit eine Aussage über deren Anpassungsgüte. Zum Schluss wurde beispielhaft für einen Patienten das Verfahren der lookup-table angewendet und die resultierende Stammzellkinetik weiter analysiert. Ergebnisse Einführend erfolgte die Analyse der resultierenden biexponentiellen Funktion mit und ohne Einbeziehung von Messunsicherheiten. Es zeigte sich, dass der Verlauf dieser Funktion besonders in Bereichen, die von einbezogenen Messunsicherheiten betroffen sind, abweichend ist. Die Beschreibung des Langzeitverlaufs erfolgt jedoch annähernd gleich. Anschließend erfolgte die Validierung der Größe des vorsimulierten Datenpool anhand eines Vergleichs der statistischen Parameter von Patienten und Simulationen. Dieser zeigte sich dabei für die weiteren Untersuchungen geeignet. Die Nutzung der lookup-table zur Identifikation der am besten zu einem Patienten passenden Therapiesimulation ist überlegen sowohl gegenüber von der Horn et al. (2013) beschriebenen als auch in dieser Arbeit neu entwickelten Regressionsverfahren. Diese ergeben deutliche Abweichungen zwischen Patientendaten und Simulation. Eine Analyse des vorhergesagten Therapieverlaufes im Stammzellkompartiment ergibt jedoch, dass ähnliche Therapieverläufe im peripheren Blut durch stark unterschiedliche Stammzellkonfigurationen beschrieben werden können. Es resultiert eine starke Streuung der vorhergesagten Zeitpunkte eines möglichen Therapieendes. Schlussfolgerungen Die Nutzung der lookup-table zu Identifikation einer passenden Therapiesimulation ist hoch effektiv und anderen Verfahren, die auf Regression basieren, überlegen. Die etablierte Computersimulation nach Roeder und Loeffler (2002) bietet Zugriff auf die Therapie in der Ebene der Stammzellen. Die in weiteren Analysen gezeigten Streuungen der vorhergesagten Therapieverläufe im Stammzellkompartiment lassen den Schluss zu, dass Methoden zur Eingrenzung der Stammzellverläufe entwickelt werden müssen, um die Vorhersagen klinisch nutzbar zu machen. Weiterhin muss anhand von Messungen an Knochenmarkproben von realen Patienten geprüft werden, ob die von der Simulation postulierten Verläufe der Tumorlast im Stammzellkompartiment der realen Behandlung entsprechen. Ausblick Die in aktuellen Arbeiten beschriebene Rolle des Immunsystems im Therapieverlauf der CML (Saussele et al. 2016; Clapp et al. 2016) sollte in eine Verbesserung des Stammzellmodells nach Roeder und Loeffler (2002) einfließen. Weiterhin kann die Validierung der im Rahmen der Individualmedizin zu treffenden Absetzvorhersagen letztendlich nur über klinische Absetzuntersuchungen ermöglicht werden
Background Chronic myeloic leukaemia (CML) is a myeloproliferative disease, which is well suited for modelling approaches. It is characterized by the oncogenic BCR-ABL1 fusion gene originating from an inverse translocation of the chromosomes 9 and 22 leading to the Philadelphia chromosome. The result is a constitutively activated tyrosine-kinase. This is followed by an extensive proliferation of leukaemic stem cells leading to a displacement of normal haematopoesis. The molecular specificity of CML forms the basis of a highly efficient, targeted therapy by tyrosine kinase inhibitors (TKIs). TKIs can decrease the tumour burden and slow down or eventually stop progressing of the disease. Currently, in clinical applications drugs are administered for the remaining life span. Interestingly, in recent treatment cessation trials patients were stopped after two years of non-detectable tumour burden and about 50% remained without relapse. The application of computer-based modelling helps to gain access to stem cell counts being difficult to measure clinically. This forms the basis for predictions of long-term therapy outcomes. Aim of this work This work aims on identifying a suitable algorithm to efficiently identify model simulations that optimally decribe individual patient kinetics. Furthermore, the clinical usability of the new methods was investigated. Material and methods The analysed group of patients was chosen out of the German cohort of the IRIS trial to ensure comparability to former investigations. It consists of 51 individuals. The course of leukaemic burden , i. e. leukaemic vs. non-leukaemic cells on a single patient level can be described as a biphasic exponential (bi-exponential) or a piecewise linear function. As an extension to former methods described by Horn et al. (2013) all parameters are included into further method development. Additionally, an investigation was conducted whether censored data points change the functional behaviour of a bi-exponential fit based on patients’ data. According to therapy data of all patients an input parameter space for the model simulation was delimited, such that all observed patient kinetics can be mimicked by the model. This parameter space was uniformly divided into 270.400 discrete parameter combinations. The therapy simulation of each combination was conducted and described by a bi-exponential function likewise to the patients’ fit. With the help of these huge variety of in silico therapies two new methods of model parameter identification for individual patients were developed. The first one is an advanced approach based on a regression model proposed by Horn et al. (2013). The second one by comparing distances between the patients’ and the models’ bi-exponential functions (lookup table). The comparison of the distances between different therapy courses (either simulated or patients’ data) was also used to compare the quality of different methods. As an example, for one patient the stem cell kinetics from the model were analysed in more detail and checked for robustness. Such a strategy, which might build the basis for clinical applications. Results A comparison between the different bi-exponential functions with and without censored data points revealed differences especially in the area in which censoring was performed. However, for the long-term tumour burden censored data had no influence. Secondly, an investigation was performed showing the sufficiency of the pre-simulated therapy courses for the new methods, i. e. lookup-table and regression models. The lookup- table turns out to be superior to identify a therapy simulation for a unique patient, since the complexity of linear regression models lead to increased deviations between patients’ therapy courses and the simulations. Unfortunately, distinct stem cell configurations lead to similar therapy descriptions in peripheral blood, assuming the correctness of the model. As a result, the prediction of a safe treatment cessation is often widely spread. Conclusions The new developed lookup-table to identify model simulations suitable for an individual patient is highly effective and superior to other methods using regression models. The simulation of the TKI treatment using the agent-based model of Roeder und Loeffler (2002) gives easy access to therapy courses on the level of leukaemic stem cells. Unfortunately, the finding of a well fitting simulation within the peripheral blood is not enough to provide a point of safe treatment cessation, since different stem cell configurations can lead to similar therapy courses. Additionally, it is necessary to check which of the assumed therapy courses on the stem cell level is appropriate. This could be done by gathering more information from bone-marrow punctures during the course of treatment. Outlook Investigations of new data showed the important role of the immune system in CML treatment (Saussele et al. 2016; Clapp et al. 2016). This should be taken into account by improving the model of Roeder und Loeffler (2002). Additionally, data from cessation trials can be used to validate the model assumptions
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McHugh, Lynsey A. « Tyrosine kinase inhibitors as adjuncts to chemotherapy in bladder cancer ». Thesis, University of Leicester, 2007. http://hdl.handle.net/2381/29860.

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Walter, Harriet Sarah. « Studies of Bruton's tyrosine kinase inhibitors in B-cell malignancies ». Thesis, University of Leicester, 2018. http://hdl.handle.net/2381/42887.

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Despite significant advances, the prognosis in relapsed/refractory (R/R) B-cell malignancies remains poor. In the Phase I study of the selective Bruton’s Tyrosine Kinase inhibitor (BTKi) tirabrutinib in R/R B-cell malignancies, I showed that targeting BTK demonstrated remarkable clinical responses and tolerability in Chronic Lymphocytic Leukaemia and Mantle Cell Lymphoma. Targeted DNA sequencing demonstrated that no mutations were associated with a lack of response in CLL. However, in activated B-cell like diffuse large B-cell lymphoma (ABC DLBCL), only 35% of patients responded to treatment and median duration of response was 12 weeks. This prompted my laboratory studies to explore mechanisms of resistance to BTKi in ABC DLBCL. Using BTKi resistant cell lines TMD8 RO and TMD8 RI, I undertook biological and genetic studies. BTK expression and subcellular localisation was not altered in the resistant cell lines. Apoptosis induced by the BTKi ibrutinib and tirabrutinib occurred 24 hours following drug exposure. A decrease in the expression of the anti-apoptotic proteins MCL1, BCLxL and BCL2A1 was observed in TMD8 but not TMD8 RO following treatment with tirabrutinib, consistent with modulation of the BCR pathway. No significant change was identified in apoptotic gene expression. Study of the BCR signalling pathway showed an increase in cell surface expression of sIgM and CD20 in the resistant cell lines. No change in IgM RNA levels nor CD20 were observed. However, gene expression of IGJ was downregulated in the resistant cell lines. Both TMD8 RO and TMD8 RI showed increased basal levels of phosphor-tyrosine phosphorylation and amplified BCR signalling following BCR ligation. Collectively, these studies indicate hyperactivation of the BCR signalling pathway in the development of resistance to BTKi, with changes occurring upstream of BTK. Further studies to characterise changes at the cell surface are required to identify novel therapeutic approaches to the development of BTKi resistance.
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Jeannot, Victor. « Identification et vectorisation de combinaisons de traitements pour la thérapie des tumeurs pulmonaires résistantes aux inhibiteurs de tyrosine kinase de l'EGFR ». Thesis, Université Grenoble Alpes (ComUE), 2015. http://www.theses.fr/2015GREAV061/document.

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Responsable d'environ 30000 décès/an en France, le cancer du poumon est un problème de santé publique majeur. Un des enjeux actuels est d'adapter le traitement du cancer du poumon pour proposer des thérapeutiques ciblées plus efficaces et moins agressives. Les inhibiteurs de l'activité tyrosine kinase du récepteur de l'EGF (EGFR-TKI, gefitinib et erlotinib) constituent un réel progrès pour le traitement des cancers du poumon. Cependant, des mécanismes de résistance ont été décrits et des traitements combinés de thérapies ciblées avec des EGFR-TKI pourraient permettre de surmonter les résistances dans les cancers du poumon.Dans ce contexte, nous avons étudié les mécanismes impliqués dans la résistance à ces traitements. Nous montrons que l'activation de la voie de signalisation PI3K/AKT joue un rôle majeur dans la résistance aux EGFR-TKI, en inhibant l'apoptose par des mécanismes dépendant de l'acétylation. Les histones déacétylases (HDACs) et les sirtuines interviennent dans ces mécanismes de résistance, en modulant l'activation de la voie PI3K/AKT et l'apoptose. Ainsi l'utilisation d'inhibiteurs des HDACs (HDACi) et des sirtuines permettent de restaurer la sensibilité aux EGFR-TKI. Ces résultats confirment l'intérêt thérapeutique de l'association EGFR-TKI/HDACi et montrent le potentiel thérapeutique d'associer des inhibiteurs de l'EGFR et de la voie PI3K/AKT pour contourner la résistance aux EGFR-TKI.Les molécules thérapeutiques doivent atteindre spécifiquement le site tumoral, nécessitant parfois de les protéger contre leur dégradation, de réduire leurs effets indésirables, et de contrôler leur libération dans le temps et l'espace, à l'aide de transporteurs. Ainsi dans la deuxième partie de cette thèse, nous avons évalué les capacités de ciblage des tumeurs pulmonaires de nanoparticules à base de copolymère amphiphile, contenant une partie polysaccharidique hydrophile (le hyaluronane) et une partie polypeptidique hydrophobe (le poly(γ‐benzyl L‐glutamate, PBLG). Nos travaux mettent en évidence la capacité de ciblage tumoral de ces nanoparticules injectées par voie intraveineuse, ouvrant ainsi de nouvelles perspectives thérapeutiques. Notre objectif est de charger les combinaisons de traitements EGFR-TKI/HDACi que nous avons identifiées dans ces vecteurs, afin de traiter les tumeurs pulmonaires résistantes aux EGFR-TKI
Responsible of 30000 deaths each year in France, lung cancer is a major public health problem. One of the current challenges is to adapt the treatment of lung cancer to offer more effective and less aggressive targeted therapies. EGFR tyrosine kinase inhibitors (EGFR-TKI, gefitinib and erlotinib) represent a real progress in lung cancer therapy. However resistance mechanisms have been described and combination of targeted therapy with EGFR-TKI could overcome resistance in lung cancer.In this context, we studied mechanisms involved in resistance to EGFR-TKI. We show that PI3K/AKT activation is a major pathway leading to EGFR-TKI resistance leading to apoptosis inhibition through acetylation-dependent mechanisms. Histone deacetylase (HADCs) and sirtuin are involved in these mechanisms and modulate PI3K/AKT activation and apoptosis. The use of HDACs inhibitors (HDACi) and sirtuins inhibitors thus restores the sensitivity to EGFR-TKI. Altogether these results confirm the therapeutic effect of the EGFR-TKI/HDACi combination and show the therapeutic potential of the association of EGFR and PI3K/AKT inhibitors to overcome EGFR-TKI resistance.Therapeutic molecules must specifically reach the tumor site, sometimes requiring to protect them against degradation, to reduce their side effects, and to control their release in time and space, using transporters. In the second part of this thesis, we have thus evaluated the lung tumors targeting capabilities of amphiphilic copolymer-based nanoparticles, containing an hydrophilic polysaccharidic block (hyaluronan) and an hydrophobic polypeptidic block (the poly(γ‐benzyl L‐glutamate PBLG). Our work highlights the tumor targeting capability of these nanoparticles injected intravenously, offering new lung cancer therapy perspectives. Our aim is to load the drugs combination (EGFR-TKI/HDACi) in these vectors, to treat the lung tumors resistant to EGFR-TKI
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Luzac, Michal Leonie. « Small Molecules as Potential Inhibitors of the Met Tyrosine Kinase Receptor ». Thesis, University College London (University of London), 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.498510.

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Myers, Samuel Harry. « Development of novel receptor tyrosine kinase inhibitors by a chemocentric approach ». Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/28769.

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In recent years, there has been a major movement in the pharmaceutical industry towards the development of molecules that selectivity inhibit a previously-validated specific target. This is referred to as target-based drug discovery. It was hoped that adopting this approach would usher in a new golden age of drug discovery. However, this has not been the case, with issues arising such as the target’s mechanism of action being poorly understood, with it not playing the expected role in the disease progression, or feedback resistance mechanisms causing the target to lose its role in the disease. In contrast to this, in the past 20 years it has been argued that developing drugs in a target-agnostic way and screening them against an expressed phenotype i.e. phenotypic drug discovery, has been more successful, despite fewer programs being run in the manner. The AXL kinase is a receptor tyrosine kinase (RTK) and a member of the TAM family, along with MER and TYRO3. AXL has long been associated with numerous types of cancer. Having been first discovered in 1991 in acute myeloid leukaemia (AML), it has gone on to be more associated with advanced solid tumours such as brain, breast, and lung, with the trend being that increased AXL correlates with a poorer prognosis for the patient. Upon the activation of AXL by the vitamin K ligand GAS6, a series of downstream pathways are activated that go on to encourage cell survival, proliferation, and migration. In addition to this, AXL has been shown to be involved in crosstalk with other kinase pathways, resulting in AXL expression being associated with chemoresistance and survival mechanisms. Despite the promising outlook for AXL inhibitors, to date only one selective AXL inhibitor, BGB324 (formally R428) has entered clinical trials, with selective AXL inhibitors being difficult to develop due to a lack of a crystal structure or a reliable homology model. To address the aforementioned issues that target-based approaches can suffer from, and due to AXL lacking a crystal structure, the work in this thesis utilised a pragmatic drug design method that started from ligands/existing scaffolds known to inhibit the target from the literature (publications, clinical trials and patents). A series of small libraries were prepared and then tested against a selected phenotype e.g. cell viability, in at least two cell types: one that expressed the target (e.g. AXL) and one that did not. Hits were optimised for potency against the desired phenotype. The compounds then went through target deconvolution (kinase screening) to confirm the target of the inhibitors. Employing this approach, we initially synthesised two small libraries of potential AXL inhibitors. The potency of these compounds was tested using cell-based phenotypic assays, by evaluating cell viability in both native and chemo-resistant breast cancer cells. These libraries were optimised through focused combinatorial synthesis and phenotypic screening, to yield a small collection of antiproliferative hits. These hits were then profiled against a panel of twelve select kinases. The first library, while giving some important structural information, did not inhibit the kinases screened in a meaningful manner. However, the second library gave several potent compounds, inhibiting AXL, FLT3, and RET, with one compound being selective for AXL. The leads from this series were optimised further, through SAR studies, gaining important structural information in order to improve potency and selectivity of the compounds. The flexibility of the phenotypic cell-based approach allowed the pursuit of FLT3 inhibitors, resulting in the synthesis of one of the most potent FLT3 inhibitors synthesised to date.
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Cooper, Margaret S. « Anti-cancer peptides containing modified tyrosine residues ». Thesis, University of Nottingham, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.246193.

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Dominguez-Escrig, J. L. « Tyrosine kinase and prenyl transferase inhibitors as potential therapeutics in urothelial carcinoma ». Thesis, University of Newcastle upon Tyne, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.427275.

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Francis, Sebastian. « Factors affecting the response to tyrosine kinase inhibitors in chronic myeloid leukaemia ». Thesis, University of Liverpool, 2015. http://livrepository.liverpool.ac.uk/2050461/.

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Chronic myeloid leukaemia (CML) is a clonal stem cell disorder characterised by the Philadelphia chromosome. The treatment and outcomes of CML patients have improved with the introduction of tyrosine kinase inhibitors (TKI). Imatinib is associated with complete cytogenetic response (CCR) rate of 71% at 12 months, as documented by large phase 3 clinical trials. I carried out a large population study in the Merseyside, Cheshire and North Wales area, which showed a maximal CCR rate of 65% over 5 years of observation. This suggests there is a higher rate of imatinib failure in a general unselected CML population compared to large clinical studies which have strict exclusion criteria. My population study also confirmed that second generation TKIs can produce high CCR rates in imatinib intolerant/resistant patients. There are a number of mechanisms of imatinib resistance. The hOCT1 transporter has been shown to be an important predictor of response to imatinib treatment. However, it has been suggested there are other drug transporters involved in imatinib transport which may have prognostic significance. This thesis examined the role of SLCO1A2, OCTN1 and OCTN2 in the transport of TKIs. Transfected cell lines expressing high levels of the respective drug transporter were made using the AMAXA nucleofection process. The cell lines with the highest gene expression, as quantified by TaqMan PCR, were then selected and used in radioactive uptake experiments. Imatinib was confirmed to be a substrate for SLCO1A2. However, the mRNA expressions levels of SLCO1A2 did not have any prognostic correlation to outcome. A review of patient co-medication also showed inhibitors of SLCO1A2 had no effect on CCR and major molecular response (MMR) rates in imatinib treated patients. OCTN1 and OCTN2 did not transport imatinib. Nilotinib and dasatinib are not substrates for SLCO1A2, OCTN1 or OCTN2. Drug drug interactions have also been implicated in drug resistance. Imatinib and metformin are actively transported by hOCT1. It was postulated that varying concentrations of metformin could potentially affect the uptake of imatinib by competitive inhibition. A metformin concentration of 768µM was required reduce imatinib uptake by 50%. However, this concentration is much higher than therapeutic metformin levels, therefore these drugs do not interact at therapeutic concentrations. This thesis shows imatinib is an effective treatment in CML but the CCR rate is lower than in published phase 3 trials. SLCO1A2 transports imatinib but RNA levels have no prognostic significance. Imatinib and metformin do not interact at normal therapeutic concentrations.
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Reiff, Sean. « Utilizing Reversible Bruton’s Tyrosine Kinase Inhibitors to Circumvent Acquired Resistance to Ibrutinib ». The Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1523372591057698.

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D'Cunha, Ronilda Raymond. « Treatment strategies to reverse efflux transporter-mediated resistance to Tyrosine kinase inhibitors ». Diss., University of Iowa, 2018. https://ir.uiowa.edu/etd/6563.

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Multidrug resistance (MDR), a phenomenon in which tumors that were initially sensitive, recur and start showing resistance not only to the initial chemotherapeutic agent but also to various anticancer drugs that are structurally and functionally different from the initial drug, constitutes one of the main reasons for the failure of chemotherapy. An important mechanism of MDR is the enhanced cellular efflux of anticancer agents due to an overexpression of ATP-binding cassette (ABC) transporters (i.e. efflux transporters), especially P-glycoprotein (Pgp), Multidrug Resistance-associated Protein 1 (MRP1) and Breast Cancer Resistance Protein (BCRP), in cancer cells. In order to reverse this resistance, there has been a lot of emphasis on the development of Pgp, MRP1 and BCRP inhibitors. Although this search has been ongoing for three decades, there are still no clinically available efflux transporter modulators. Tyrosine kinase inhibitors (TKIs) are a novel, rapidly growing class of anticancer agents that have a target-based mechanism of action, and their use transformed cancer chemotherapy due to higher specificity and enhanced safety profiles compared to conventional chemotherapeutic agents. Despite their tremendous success in treating various types of tumors, patients develop resistance to TKIs over time. Most of the FDA- approved TKIs are substrates of Pgp and/or BCRP, and as a result, these efflux transporters are also an important cause of conferred resistance against TKIs in cancer cells. Additionally, none of the 31 approved TKIs have an indication for use in brain tumors and interestingly, this may also due to the presence of Pgp and BCRP at the blood-brain barrier (BBB) and in the tumor cells, which prevent the TKI from crossing the BBB and reaching its target tumor site. Since Pgp- and BCRP- mediated TKI efflux has been shown to be involved in TKI resistance, the inhibition of these transporters could represent a potential TKI resistance reversal strategy. Over the last three decades, a large number of Pgp and/or BCRP inhibitors have been identified, but none of them have successfully made it to the clinic. It was observed that most drugs identified as inhibitors were either unable to achieve Pgp and BCRP inhibitory concentrations in-vivo without imparting severe toxicity, or did not possess adequate bioavailability and tissue distribution profiles in order to reach the tumor site. From these identified candidate inhibitors, after much thought and consideration, we chose to investigate TKIs and methylated flavones as modulators of efflux transporter-mediated TKI resistance. The overall goal of this project was to investigate the promising chemosensitizing potential of TKIs and methylated flavones in efflux transporter-mediated TKI resistance, both in-vitro and in-vivo. To identify potent efflux transporter inhibitor TKIs, we evaluated the effect of various TKIs on the accumulation of afatinib, the model TKI substrate, in Pgp- and BCRP- overexpressing cell lines. Afatinib was chosen as the model TKI substrate for our study because it undergoes very minimal metabolism in several species. Afatinib is a substrate of both Pgp and BCRP, but is not a substrate of uptake transporters. Therefore, it was anticipated that an in-vivo efflux transporter-mediated interaction with afatinib would most likely not be confounded or masked by other factors influencing its disposition. From the in-vitro cell uptake studies, we found that nilotinib is a potent inhibitor of both Pgp and BCRP, and it reversed Pgp- and BCRP- mediated afatinib efflux. Subsequently, an in-vivo study was carried out in mice to investigate the interaction between afatinib and nilotinib; and also the impact of nilotinib on the pharmacokinetics and tissue distribution of afatinib. Afatinib exposure in the plasma and in most tissues, namely liver, lung, kidney, heart, muscle, fat, and skin, was found to be significantly increased when nilotinib was coadministered with afatinib. Further, the nilotinib concentrations in most mice tissues was above that needed for Pgp and BCRP inhibition. These results showed that nilotinib could be a potent chemosensitizing agent for Pgp- and BCRP- mediated TKI resistance. Additionally, a significant increase in afatinib brain exposure was observed in the mice which were administered afatinib in combination with nilotinib. This is an interesting and important finding that could potentially be very useful in the treatment of primary and metastasized brain tumors. We also developed a physiologically based pharmacokinetic model of afatinib to characterize its tissue disposition in mice organs, and this model was then scaled up to humans. The developed model accurately predicted afatinib plasma exposure in healthy volunteers and patients with solid malignant tumors, renal impairment, and hepatic impairment. To investigate the chemosensitizing potential of methylated flavones in efflux transporter-mediated TKI resistance, the Bcrp1 inhibitory effect of 5,7-DMF and its effect on sorafenib accumulation was evaluated in-vitro. 5,7- DMF was found to be a potent inhibitor of Bcrp1 and consequently, its impact on the pharmacokinetics and tissue distribution of sorafenib was evaluated in mice. Results showed that co-administration with 5,7-DMF led to significantly greater sorafenib exposure in plasma and in most tissues collected. This indicated that 5,7-DMF may represent a promising chemosensitizing agent for Bcrp1-mediated TKI resistance due to its low toxicity and potent Bcrp1 inhibition. Our results may have important clinical implications as TKIs are currently the most widely used anticancer agents. 5,7-DMF may show great potential in reversing MDR in tumors expressing BCRP. On the other hand, TKI-TKI combination therapy, especially with nilotinib as the perpetrator, is an attractive strategy to combat both Pgp- and BCRP-mediated TKI resistance. Additionally, since nilotinib has a wide volume of distribution and can reach various tissues at concentrations sufficient enough to inhibit Pgp and BCRP; it could potentially be used as a chemosensitizer in the treatment of numerous types of cancers. Furthermore, its chemosensitizing potential could particularly be useful in the treatment of primary and metastatic brain tumors. Further studies are warranted to assess the chemosensitizing effect of nilotinib in tumor xenograft models.
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Bibi, Siham. « Nouvelles approches thérapeutiques au cours des mastocytoses systémiques avancées KIT D816V+ résistantes aux inhibiteurs de tyrosine kinases ». Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLS551.

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Les mastocytoses systémiques (SM) constituent un groupe hétérogène de maladies rares, caractérisées par l’accumulation anormale de mastocytes malins dans la moelle osseuse et dans d’autres organes extra-cutanés. La majorité des patients avec SM ont une mutation activatrice du gène KIT, le plus souvent la mutation KIT D816V, retrouvée chez plus de 90% de tous les patients. Cette mutation induit l’activation constitutive du récepteur KIT en déclenchant de façon aberrante une cascade de voies de signalisation, dont la voie PI3K/AKT et JAK/STAT5, aboutissant à l’inhibition de l’apoptose et à l’augmentation de la prolifération et de la survie des mastocytes malins. Cependant, l’efficacité des inhibiteurs de tyrosines kinases (ITKs) sur cette mutation est limitée à cause de la résistance et/ou de toxicité liée à un manque de spécificité. Il est donc nécessaire de trouver de nouvelles approches thérapeutiques afin de contourner cette résistance au cours des SM KIT D816V+ avancées. Nous avons utilisé une approche consistant à cibler de façon combinée des molécules activées en aval de KIT D816V, comme AKT et STAT5, par des inhibiteurs pharmacologiques. Ceci nous a permis d’identifier une combinaison synergique entre un inhibiteur d’AKT (GSK690693) et un inhibiteur de STAT5 (BP-1-102). Ces composés sont capables d’inhiber la prolifération des cellules KIT D816V+ seuls ou en combinaison, mais à de très fortes concentrations, malheureusement non utilisables en thérapeutique. Néanmoins, ces premiers résultats ont permis de valider AKT et STAT5 comme cibles potentielles dans le traitement des SM avancées. La seconde approche employée a été de cibler directement le récepteur KIT D816V par des inhibiteurs pharmacologiques. A l’issu d’un criblage, nous avons identifié trois composés - BLU2317, BLU2718 et DCC-2618 - capables d’inhiber sélectivement la phosphorylation de KIT D816V. Ces composés inhibent la prolifération des cellules ROSAKIT D816V et HMC-1.2, et induisent l’apoptose des cellules de façon dose-dépendante. Bien que les effets de ces trois composés soient similaires, DCC-2618 agit à des concentrations plus faibles par rapport aux composés BLU2317 et BLU2718. Afin d’apprécier l’efficacité in vivo de DCC-2618, nous avons d’abord établi un nouveau modèle de SM basé sur l’injection intraveineuse des cellules ROSAKIT D816V-Gluc exprimant la Gaussia luciferase (Gluc) dans des souris NSG. La présence de la Gluc sécrétée par les cellules ROSAKIT D816V-Gluc facilite la mise en évidence de prise de greffe et permet un contrôle précis de la progression de la maladie. Ce modèle reproduit, au bout de 4 semaines, chez toutes les souris greffées, une SM avancée similaire à celle retrouvée chez l’homme, avec atteinte de la moelle osseuse, du sang, de la rate et du foie, tandis que la dégradation de l’état général des souris n’est observée qu’à partir de 12 semaines. Ce nouveau modèle offre suffisamment de temps pour explorer la cinétique de la progression de la maladie et surtout pour effectuer des études pharmacologiques précliniques. L’évaluation de l’effet de DCC-2618 in vivo a été réalisée sur ce modèle. Etonnamment, DCC-2618 n’a pas été capable d’inhiber la progression de la maladie chez les souris traitées, bien qu’atteignant des concentrations élevées dans la moelle osseuse et le plasma des souris traitées. Néanmoins, DCC-2618 s’est montré capable d’inhiber la phosphorylation de KIT dans les cellules issues de la moelle osseuse des souris traitées. En revanche, contrairement aux effets observés in vitro, DCC-2618 a induit une surexpression de phospho-ERK1/2 dans les cellules malignes des souris greffées. Ceci suggère qu’ERK1/2 joue un rôle important dans la résistance au composé DCC-2618 et éventuellement à d’autres ITKs, indépendamment du récepteur KIT. ERK1/2 pourrait donc être une nouvelle cible thérapeutique d’intérêt dans le traitement des SM résistantes aux ITKs
Systemic mastocytosis (SM) is a heterogeneous group of rare diseases characterized by abnormal accumulation of malignant mast cells (MCs) in the bone marrow (BM) and other extra-cutaneous organs. The majority of SM patients have an activating mutation in the KIT gene, usually the D816V point mutation, which is found in more than 90% of all patients. This mutation induces constitutive activation of the KIT receptor by triggering a cascade of signaling pathways, including the PI3K/AKT and the JAK/STAT5 pathways, resulting in the inhibition of apoptosis and increased survival and proliferation of malignant mast cells. However, the efficacy of the tyrosine kinase inhibitors (TKIs) on this mutation is limited due to resistance and/or toxicity associated with a lack of specificity. It is therefore critical to find new therapeutic approaches to overcome this resistance to TKIs, particularly for advanced KIT D816V+ SM. In the present thesis, we have used an approach consisting in targeting molecules activated downstream of KIT D816V, such as AKT and STAT5, using pharmacological inhibitors in combination. This allowed us to identify a synergistic combination of an AKT inhibitor (GSK690693) and an inhibitor of STAT5 (BP-1-102). These compounds are able to inhibit proliferation of KIT D816V+ cells, alone or in combination, but at very high concentrations, unfortunately not useful therapeutically. Nevertheless, these initial results have validated STAT5 and AKT as potential targets for the treatment of advanced SM. The second approach used was to target directly the KIT D816V receptor by pharmacological inhibitors. After a large screening, we identified three compounds - BLU2317, BLU2718 and DCC-2618 - which selectively inhibit the phosphorylation of KIT D816V. These compounds inhibit the proliferation of ROSAKIT D816V and HMC-1.2 cells, and induce apoptosis of these cells in a dose-dependent manner. Although the effects of these three compounds are similar, the DCC-2618 compound acts at lower concentrations relative to BLU2317 and BLU2718 compounds. In order to assess the in vivo efficacy of DCC-2618, we first established a new model of SM based on intravenous injection of cells expressing Gaussia luciferase (Gluc), ROSAKIT D816V-Gluc cells, in NSG mice. The presence of the secreted Gluc in ROSAKIT D816V-Gluc cells facilitates the detection of engraftment and allows precise monitoring of disease progression. This model reproduced within four weeks, in all grafted mice, an advanced SM similar to the one found in humans, with neoplastic MCs infiltration in BM, blood, spleen and liver, while the terminal deterioration of the clinical condition of the mice was observed after 12 weeks. Thus, this new in vivo model allows modulating the aggressiveness of the disease by varying the number of injected cells. It provides sufficient time to explore the kinetics of disease progression and especially to conduct preclinical pharmacological studies. We then evaluated the effect of DCC-2618 compound in vivo on this model. Surprisingly, DCC-2618 was not able to inhibit disease progression in treated mice, although it reached high concentrations in the BM and the plasma of treated mice. Nevertheless, we showed that the compound was able to inhibit the phosphorylation of the KIT receptor in cells derived from the BM of treated mice. In addition, contrasting to the effects observed in vitro, DCC-2618 induced an over-expression of phospho-ERK1/2 in the malignant cells of transplanted mice. This suggests that ERK1/2 may play a critical role in the resistance to DCC-2618, and possibly to other TKIs, independently of the KIT receptor. ERK1/2 could thus be a new interesting therapeutic target in the treatment of advanced SM resistant to TKIs
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24

Dillon, Anne M. R. « An investigation of protein tyrosine phosphorylation in equine blood platelets ». Thesis, University of Cambridge, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.390250.

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Knights, Victoria E. E. « Tumour cell responses to novel fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitors ». Thesis, University of Cambridge, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.608393.

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Filho, Pedro Aurio Maia. « Genotoxicity and mutagenicity in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors ». Universidade Federal do CearÃ, 2017. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=19044.

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Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico
Chronic myelogenous leukemia (CML) is a myeloproliferative disease of hematopoietic stem cells, characterized by the presence of the Philadelphia (Ph) chromosome, originating from a reciprocal translocation between the long arms of chromosomes 9 and 22, forming the gene BCR-ABL, which encodes a BCR-ABL oncoprotein with constitutive tyrosine kinase activity. The clinical course of CML is often divided into three phases: chronic, accelerated, and blast. The treatment of choice for the chronic phase is the first-generation tyrosine kinase inhibitor (TKI), imatinib mesylate, and for refractory patients, second-generation TKIs (dasatinib or nilotinib) are used. Studies have shown that residual leukemia may persist even in the best responders to TKI, since therapy is not curative. In this context, the present study aimed to evaluate the genotoxicity and mutagenicity of TKI in patients with CML followed at the hematology clinic of the Walter CantÃdio University Hospital (HUWC). It is a cross-sectional study with 44 patients with clinical and molecular diagnosis of CML. Patients were stratified into three groups: diagnosis (CML D) (n = 5), use of first generation TKI (CML) (n = 31) and use of second generation TKI (CML) (n = 8). The control group (CG) consisted of apparently healthy individuals. Genotoxicity and mutagenicity were analyzed by the comet assay and micronucleus test. Statistical analysis of the data was performed using the GraphPad Prism 6.0 program using the Kruskal-Wallis or ANOVA, Mann Whitney or T-student tests, depending on the normality of the data and the level of significance was 5% (p < 0.05). Patients with CML had a statistically higher ADN damage index (DI) compared to CG (p < 0.0001). When the patients were stratified, a progressive increase of the DNA ID was verified in the groups: CML D, CML G1 and CML G2, respectively, relative to GC (p < 0.05). Patients with CML had a statistically higher micronucleus index (NMI), nucleoplasmic bridge index (NPI) and nuclear bud index (NBI) compared to the CG (p < 0.05). By stratifying patients with CML, it was found that patients in the G1 and G2 CML groups had statistically higher NMI and NPI compared to CG (p <0.001). NMI was also elevated in the CML G2 group in relation to the patients in the CML D group (p <0.01). The nuclear bud index (NBI) did not present statistical difference in the analyzes performed after the stratification of the groups. The TKI revolutionized CML therapy, improving patient survival. However, these results point to the relevance of studies that evaluate the possible genotoxic and mutagenic effects of this therapy in the long term. The mechanisms involved should be elucidated for the purpose of improving treatment as well as assessing the clinical impact this harm may cause.
A leucemia mielÃide crÃnica (LMC) à uma doenÃa mieloproliferativa das cÃlulas-tronco hematopoÃticas, caracterizada pela presenÃa do cromossomo Philadelphia (Ph), originado a partir de uma translocaÃÃo recÃproca entre os braÃos longos dos cromossomos 9 e 22, formando o gene BCR-ABL, que codifica uma oncoproteÃna BCR-ABL com atividade tirosino-quinase constitutiva. O curso clÃnico da LMC à frequentemente dividido em trÃs fases: crÃnica, acelerada e blÃstica. O tratamento de escolha para a fase crÃnica à o inibidor de tirosino-quinase (ITK) de primeira geraÃÃo, mesilato de imatinibe, e para os pacientes refratÃrios, utiliza-se os ITK de segunda geraÃÃo (dasatinibe ou nilotinibe). Estudos tÃm demonstrado que a leucemia residual pode persistir mesmo nos melhores respondedores aos ITK, uma vez que a terapia nÃo à curativa. Nesse contexto, o presente estudo objetivou avaliar a genotoxicidade e mutagenicidade dos ITK em pacientes com LMC acompanhados no ambulatÃrio de hematologia do Hospital UniversitÃrio Walter CantÃdio (HUWC). Trata-se de um estudo transversal com 44 pacientes com diagnÃstico clÃnico e molecular de LMC. Os pacientes foram estratificados em trÃs grupos: ao diagnÃstico (LMC D) (n=5), em uso de ITK de primeira geraÃÃo (LMC G1) (n=31) e em uso de ITK de segunda geraÃÃo (LMC G2) (n=8). O grupo controle (GC) foi composto por indivÃduos aparentemente saudÃveis. A genotoxicidade e mutagenicidade foram analisadas atravÃs do ensaio cometa e teste de micronÃcleos. A anÃlise estatÃstica dos dados foi realizada atravÃs do programa GraphPad Prism 6.0 utilizando-se os testes de KruskalâWallis ou ANOVA, Mann Whitney ou T-student, dependendo da normalidade dos dados e o nÃvel de significÃncia foi de 5% (p < 0,05). Pacientes com LMC apresentaram Ãndice de dano (ID) no DNA estatisticamente mais elevado em comparaÃÃo ao GC (p < 0,0001). Quando os pacientes foram estratificados, foi verificado um aumento progressivo do ID no DNA nos grupos: LMC D, LMC G1 e LMC G2, respectivamente, em relaÃÃo ao GC (p < 0,05). Pacientes com LMC apresentaram Ãndice de micronÃcleos (IMN), Ãndice de pontes nucleoplasmÃticas (IPN) e Ãndice de buds nucleares (IBN) estatisticamente mais elevados em comparaÃÃo com o GC (p < 0,05). Ao se estratificar os pacientes com LMC, foi verificado que pacientes dos grupos LMC G1 e G2 apresentaram IMN e IPN estatisticamente mais elevados em comparaÃÃo ao GC (p < 0,001). O IMN tambÃm foi elevado no grupo LMC G2 em relaÃÃo aos pacientes do grupo LMC D (p < 0,01). O Ãndice de bud nuclear (IBN) nÃo apresentou diferenÃa estatÃstica nas anÃlises realizadas apÃs a estratificaÃÃo dos grupos. Os ITK revolucionaram a terapia da LMC, melhorando a sobrevida dos pacientes. No entanto esses resultados alertam para a relevÃncia de estudos que avaliem os possÃveis efeitos genotÃxicos e mutagÃnicos dessa terapia a longo prazo. Os mecanismos envolvidos devem ser elucidados com a finalidade de aprimorar o tratamento, bem como avaliar o impacto clÃnico que esse dano pode causar.
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Gregory, T., et John Bossaer. « Pharmacogenomics Guided Dosing of Tyrosine Kinase Inhibitors in a Patient with Renal Cell Carcinoma ». Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/etsu-works/7796.

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Cytochrome P450 (CYP) enzymes play a crucial role in the human body. These enzymes are responsible for the synthesis of steroid hormones and cholesterol, as well as the metabolism of external substances such as medications. While more than 50 CYP enzymes have been identified, just 6 are credited with metabolizing most drugs. Of note is CYP 3A4, which metabolizes ~34% of medications that use the CYP enzyme system. CYP enzymes are polymorphic, meaning there are different versions of the same enzyme; therefore there is variability from individual to individual in their ability to metabolize medications. In the oncology field tyrosine kinase has been identified as an important target controlling cell regulatory functions and proliferation. Thus, tyrosine kinase inhibitors have become widely used for a variety of malignancies. Many of these tyrosine kinase inhibitors rely on CYP 3A4 for metabolism and are subject to variable toxicities based on an individual patient’s genome. A 62-year-old female was diagnosed with Renal Cell Carcinoma (RCC). After undergoing a left nephrectomy, a surveillance scan 21 months after diagnosis was concerning for metastatic disease, which was then confirmed through biopsy. The patient was started on sunitinib 50 mg on days 1-28 of a six-week cycle for metastatic RCC. The patient suffered from Grade 3 myelosupression/mucositis within two weeks of the initiation of therapy. The early onset and severity of the toxicity lead to CYP 3A4 pharmacogenetic testing. She was subsequently found to have a 3A4 polymorphism (*1/*28). The dose of sunitinib was reduced to 25 mg followed by a further reduction to 12.5 mg due to toxicity. Eighteen months after starting sunitinib, a CT scan showed disease progression and therapy was changed to pazopanib. Due to her 3A4 polymorphism, the starting pazopanib dose was empirically reduced by 50% and was started at 400 mg/daily. Pazopanib was held for episodes of severe diarrhea and was further reduced to 200 mg/daily. Nine months after starting pazopanib, new imaging showed lesions in the patient’s liver, confirming disease progression. The patient was subsequently started on nivolumab but quickly progressed. She was then started on cabozantinib at a dose reduced 20 mg/daily. This initial dosing was tolerated well by the patient, so a decision was made to alternate between 20 and 40 mg/daily to increase to an average of 30 mg/daily. She is currently tolerating the 30 mg/daily and continues treatment for metastatic RCC. As described above, CYP 3A4 polymorphisms can result in severe toxicities that present earlier in the treatment course than traditionally expected. Moving forward there may be a role in testing for these polymorphisms to determine an individual’s optimal dose before initiating therapy with tyrosine kinase inhibitors. The advantage of performing such testing would be to limit the severity of toxicities experienced by this patient population, while retaining the overall benefit of these medications.
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Johnston, Rosie Arwen. « Implications of interactions between tyrosine kinase inhibitors and human solute carriers in cancer therapy ». Thesis, The University of Sydney, 2013. http://hdl.handle.net/2123/10522.

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Members of the solute carrier (SLC) family of transporters govern the cellular influx of a multitude of endogenous compounds, xenobiotics and drugs. SLCs including organic anion transporting polypeptide (OATP) 1A2 (SLCO1A2), OATP1B3 (SLCO1B3) and organic cation transporter (OCT) 1 (SLC22A1) participate in the disposition of several anticancer drugs, such as the tyrosine kinase inhibitor (TKI) imatinib. Some of these agents may elicit drug-drug interactions (DDIs) during therapy, so the accumulation of pharmacokinetic data concerning TKIs is of clinical interest. In this project, the impact of TKIs on the uptake of model substrates in cells overexpressing SLC transporters was evaluated. Human embryonic kidney 293 (HEK293) cells were transfected with complementary DNA to express transport proteins. TKIs (10 μM) were then tested for their capacity to inhibit the uptake of a specific transporter-mediated radiolabelled substrate into these cells. Half maximal inhibitory concentrations (IC50) and inhibition constants (Ki) of potent inhibitors were determined. Of the 13 clinically relevant TKIs tested, 11 effectively inhibited substrate uptake by some transporters. Two interactions had IC50 and Ki values in the nanomolar range: the inhibition of OATP1A2- and OATP2B1-mediated estrone-3-sulfate uptake by cediranib and erlotinib, respectively. Potent inhibitory interactions were recommended for further clinical DDI studies.
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Contini, A. « Synthesis, in silico and pharmacological evaluation of 2-pyridin-acetamides as tyrosine kinase inhibitors ». Doctoral thesis, Università degli Studi di Milano, 2003. http://hdl.handle.net/2434/174341.

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A new synthesis of 2-pyridineacetamides was developed starting from pyran-2-one N-functionalized amidines. Secondary amines reacted in a sealed tube with the above-mentioned amidines and, by nucleophilic attack on pyran-2-one nucleus and thermal rearrangement, afforded exclusively the desired 2-pyridineacetamide derivatives. Such compounds have been pharmacologically tested on smooth muscular cells proliferation and resulted active with an IC50 ranging from 40 to 0.7 µM. With the aid of molecular modeling tools a potential mechanism of action has been proposed. The pharmacological activity seems to be due to tyrosine kinase receptors inhibition. In silico experiments shows a notable selectivity toward the epidermal derived growth factor receptor kinase (EGFRK) and the platelet derived growth factor receptor kinase (PDGFRK) if compared with the vascular endothelial derived growth factor receptor kinase (VEGFRK) and the fibroblast derived growth factor receptor kinase (FGFRK). The predicted potency of the 2-pyridineacetamides described in the present study is comparable to that of known EGFRK inhibitor TarcevaTM. Preliminary pharmacological experiments conducted on rat's aorta smooth muscular cells confirm the observed computational results.
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Junker, Bernd. « Lokale Therapie der Sauerstoff-induzierten angioproliferativen Retinopathie im Mausmodell small molecule receptor tyrosine kinase inhibitors / ». [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=971428387.

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Abe, Mineo. « Development of peptide inhibitors of the receptor tyrosine kinase activity in a novel inhibitory mechanism ». 京都大学 (Kyoto University), 2010. http://hdl.handle.net/2433/120515.

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Nuseibeh, Samir. « Modulation of mucin expression in respiratory epithelial cells : effect of ErbB receptor tyrosine kinase inhibitors ». Thesis, Imperial College London, 2009. http://hdl.handle.net/10044/1/8229.

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Secretion of mucins (e.g. MUC5AC) by the airway epithelium into the respiratory tract mucus layer is an important homeostatic mechanism which safeguards the lung from invasive pathogens and harmful particles. Airway mucus hypersecretion features in the pathophysiology of inflammatory-based airway diseases such as chronic obstructive pulmonary disease (COPD) and asthma. Signalling of the ErbB receptor tyrosine kinase subfamily, particularly the ErbB1 and ErbB2 receptor subtypes, has been implicated in the process of airway mucus hypersecretion, and upregulation of ErbB1 receptor occurs in the lungs of asthmatics, COPD sufferers, and cigarette smokers. Thus, ErbB receptor tyrosine kinase inhibitors (RTKIs) offer a potential treatment for airway mucus hypersecretion. This thesis studied the effects of five such inhibitors; an ErbB1, an ErbB2, and three dual ErbB1+B2 inhibitors, in an in vitro system of mucin synthesis using NCI-H292 cells - a carcinoma-based lung epithelial cell line. After pharmacological characterisation of the NCI-H292 cell in vitro system, Taqman RT-qPCR was used to measure the effect of the five inhibitors on EGF-induced MUC5AC mRNA expression (as a marker of mucin synthesis). The effect of the five ErbB RTKIs on cell proliferation was also measured (as a positive control) by analysing DNA synthesis. All five inhibitors attenuated DNA synthesis with similar potencies suggesting all drugs were pharmacologically active, but only the single ErbB1 RTK inhibitor attenuated EGF-induced MUC5AC mRNA expression. To address the discrepancy in pharmacological activity between the five ErbB RTKIs, activity of the ERK1/2-dependent signal pathway involved in ErbB receptor-mediated MUC5AC synthesis was analysed by measuring ErbB receptor autophosphorylation (measuring phosphorylation of four specific tyrosine residues involved in ERK1/2 induction) and ERK1/2 phosphorylation by Western blot or ELISA. Although all five ErbB RTKI compounds inhibited ErbB1 and ErbB2 receptor autophosphorylation to some extent (particularly at 10 μM), only the single ErbB1 RTK inhibitor convincingly inhibited autophosphorylation of all four tyrosine residues implicated in ERK1/2 signalling. Most importantly, the single ErbB1 RTK inhibitor was the only inhibitor to block downstream phosphorylation of ERK1/2. The reason for the varying potencies exhibited by the five ErbB1 RTK inhibitors was unclear but most likely reflects a difference in the pharmacological properties (for example, the receptor dissociation rate) of each compound. These data indicate that selective ErbB1 RTK inhibitors would be of therapeutic benefit for the airway mucus hypersecretion of asthma and COPD.
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Hähnel, Tom, Christoph Baldow, Joëlle Guilhot, François Guilhot, Susanne Saussele, Satu Mustjoki, Stefanie Jilg et al. « Model-based inference and classification of immunological control mechanisms from TKI cessation and dose reduction in CML patients ». American Association for Cancer Research (AACR), 2020. https://tud.qucosa.de/id/qucosa%3A74320.

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Recent clinical findings in chronic myeloid leukemia (CML) patients suggest that the risk of molecular recurrence after stopping tyrosine kinase inhibitor (TKI) treatment substantially depends on an individual’s leukemia-specific immune response. However, it is still not possible to prospectively identify patients that will remain in treatment-free remission (TFR). Here, we used an ordinary differential equation (ODE) model for CML, which explicitly includes an anti-leukemic immunological effect and applied it to 21 CML patients for whom BCR-ABL1/ABL1 time courses had been quantified before and after TKI cessation. Immunological control was conceptually necessary to explain TFR as observed in about half of the patients. Fitting the model simulations to data, we identified patient-specific parameters and classified patients into three different groups according to their predicted immune system configuration ('immunological landscapes”). While one class of patients required complete CML eradication to achieve TFR, other patients were able to control residual leukemia levels after treatment cessation. Among them were a third class of patients, that maintained TFR only if an optimal balance between leukemia abundance and immunological activation was achieved before treatment cessation. Model simulations further suggested that changes in the BCR-ABL1 dynamics resulting from TKI dose reduction convey information about the patient-specific immune system and allow prediction of outcome after treatment cessation. This inference of individual immunological configurations based on treatment alterations can also be applied to other cancer types in which the endogenous immune system supports maintenance therapy, long-term disease control or even cure.
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Aljohani, Hashim M. « Targeting Tyrosine Kinase Drug Resistance Mechanisms and Metastatic Pathways in Brain Tumors ». University of Cincinnati / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1595846160285645.

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Lella, Divya Jyothi. « Functionalization and Modification of Naphthaquinone Analogs as HER2 Kinase Inhibitors ». TopSCHOLAR®, 2014. http://digitalcommons.wku.edu/theses/1325.

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HER2 overexpression in breast cancer tumors predicts lower overall survival. Because of the aggressive nature of HER2 tumors and the association with metastatic disease, the HER2 receptor holds great promise as a therapeutic target in metastatic breast cancer. We are developing small molecule inhibitors that bind to the ATP binding site of the tyrosine kinase domain in order to inhibit tyrosine auto-phosphorylation. This process controls biological pathways that mediate the cell growth. In normal cells this process is highly controlled. We are targeting the modification of the side chain of the hydroxy methyl group of 2-Hydroxy methyl-5,8-dimethoxy-1,4-naphthaquinone. These compounds should inhibit the tyrosine kinase cascade of reactions thereby suppressing the overexpression of HER2 shutting down the tumor growth. The synthesis and characterization of a series of substituted naphthaquinone analogs with different increasing chain lengths will be reported.
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Broadbridge, Robert James. « Design and synthesis of novel inhibitors to the SH2 domain of the protein tyrosine kinase p56lck ». Thesis, University of Southampton, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.494712.

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Grockowiak, Élodie. « Role of the Bone Morphogenetic Proteins pathway in tyrosine kinase inhibitors resistance in Chronic Myeloid Leukemia ». Thesis, Lyon, 2017. http://www.theses.fr/2017LYSE1253.

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La leucémie Myéloïde Chronique est un néoplasme myéloprolifératif causé par l'expression de la kinase oncogène BCR-ABL. Les Inhibiteurs de Tyrosine Kinase (ITK) spécifiques de BCR-ABL ont révolutionné la prise en charge de la maladie. Les ITK ne sont cependant pas curatifs ; en effet, certaines cellules souches leucémiques (CSL) sont résistantes aux ITK, et persistent dans la moelle osseuse des patients même en rémission prolongée. Ces CSL sont probablement responsables de la rechute chez 60% de ces patients après arrêt des ITK. 30% des patients développent une résistance aux ITK via des mécanismes inconnus. Dans un contexte sain, les Bone Morphogenetic Proteins (BMP) régulent différentes propriétés des cellules souches hématopoïétiques. Nous avons mis en évidence que les patients atteints de LMC présentent une altération de la voie BMP avant leurs mises sous traitement, avec une hausse de l'expression du récepteur dans les cellules leucémiques immatures, amplifiée par de forts taux de BMP2/4 produits par le microenvironnement des CSL, la niche. Ici, nous démontrons que ces altérations sont maintenues chez les patients sous traitement, et sont activement impliquées dans la résistance aux ITK. Les patients résistants présentent une surexpression de BMPR1b dans les CSL et un maintien de forts taux de BMP produits à la fois par les cellules leucémiques mais aussi par les cellules stromales. Les BMP permettent la survie des CSL via l'expression du récepteur BMPR1b et induisent l'expression de TWIST-1, un facteur de transcription précédemment identifié par l'équipe comme induisant la résistance
Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm caused by the expression of the oncogenic protein kinase, BCR-ABL. The Tyrosine Kinase Inhibitors (TKI) specifics of BCR-ABL kinase dramatically changed the outcome of CML, turning a life-threatening disease into a chronic illness. However, TKI are not yet curative since most CML patients still retain progenitors and leukemic stem cells (LSC) in bone marrow permanently. Thus, approximately 60% of patients that achieve Complete Molecular Remission =2 years relapse following TKI withdraw. Moreover, some patients develop true resistance to TKI, with ~30% due to unknown mechanisms. In chronic phase CML (CP-CML), LSC survive, sustain interactions with their niche where resistance mechanisms can occur, responsible for disease persistence and relapse following treatment cessation. In normal bone marrow, Bone Morphogenetic Proteins (BMP) pathway regulate the fate and proliferation of normal hematopoietic stem cells, as well as interactions with their niche. The deregulations of this pathway drive early steps of CML development. In newly diagnosed CP-CML patients, high concentration of BMP2/4 in the leukemic niche allows LSC maintenance and sustains a permanent pool of leukemic progenitors expressing elevated levels of BMPR1b receptor. Here, we report that alterations of the BMP pathway persist in TKI-CML resistant patients. As compared to patients in Complete Cytogenetic Remission (CCyR), cells isolated from TKI-resistant patients display a high level of BMPR1b expression in immature cells and high levels of BMP2/4 in bone marrow, provided by the niche and by the leukemic immature cells themselves. BMP allow leukemic stem cells resistance to treatments through binding to BMPR1b. Interestingly, BMP2/4-treated cells overexpressed TWIST-1, a transcription factor that we previously identified as a predictive factor of CML resistance
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Šramel, Peter. « A synthesis and biological screening of predicted inhibitors of Tyrosine Kinases, e.g. KDR, designed in silico ». Thesis, Strasbourg, 2017. http://www.theses.fr/2017STRAF064.

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Les protéines kinases représentent le groupe d'enzymes qui servent d'intermédiaire pour la phosphorylation de protéines - le transfert d'un groupe phosphate de l'adénosine triphosphate(ATP) sur des chaînes latérales correspondantes de tyrosine, de serine ou de thréonine des acides aminées. La phosphorylation de protéines est un des outils les plus importants pour la régulation de l'activité cellulaire. La « signalisation » cellulaire par le récepteur de tyrosine kinase VEGFR2 (KDR) appartient aux réactions biochimiques clés influençant la croissance de tumeurs. L'inhibition thérapeutique de cette réaction à l'aide des composés de faible poids moléculaire spécifiques est devenue une stratégie utile dans le cadre des thérapies anticancéreuses. Ce travail a amené à la découverte de 16 substances biologiquement actives sur la base N,5-diaryloxazol-2-amine (IC50, VEGFR2 TK). D'excellents résultats ont été atteints notamment dans le cas des substances 189, 191, 211, 214, 220, 221, 223 et 4 qui montrent une activité inhibitrice inférieure à 500 nM
Protein kinases represent a group of enzymes responsible for phosphorylation - transfer of aphosphate group from adenosine triphosphate (ATP) to tyrosine or serine/threonine residues. Protein phosphorylation is one of the most important tools regulating a cell activity. A cell "signalization" through an endothelial receptor tyrosine kinase VEGFR2 TK (KDR) is the important pathway influencing growth of a tumor. Small-molecule inhibitors of VEGFR2 TK (VEGFR2 TKls) have become an important tool for the treatment of various types of cancer. This dissertation thesis resulted in a discovery of 16 biologically active N,5-diaryloxazol-2-amines (IC50, VEGFR2 TK). Very good results were achieved especially with compounds 189, 191, 211, 214, 220, 221, 223 and 4 exhibiting the activity under 500 nM
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Atatreh, Noor Aldeen S. A. « Design, synthesis and evaluation of inhibitors for Src tyrosine kinase and their impact on colorectal cancer cells ». Thesis, University of Manchester, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.492836.

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Colorectal cancer is the highest cause of cancer-related death in the West. c-Src protein levels are elevated in colon cancer cells compared to non-malignant cells, In addition, Src signalling and transduction are directly involved in cell growth, cell cycle, malignant transformation and cell migration, providing opportunities for inhibition of Src.
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Rogers, Susanne Jane. « Towards the Mechanistic Effects of Tyrosine Kinase Inhibitors in Squamous Cell Carcinoma of the Head and Neck ». Thesis, Institute of Cancer Research (University Of London), 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.516267.

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Bhosle, J. « Modulation of DNA strand break induction and repair by tyrosine kinase inhibitors targeted against EGFR and HER2 ». Thesis, University College London (University of London), 2012. http://discovery.ucl.ac.uk/1344180/.

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Purpose: The human epidermal growth factor receptors EGFR (erbB1) and HER2 (erbB2/neu) are involved in mediating resistance to chemotherapy and ionising radiation (IR). In vitro studies demonstrate that small molecule tyrosine kinase inhibitors (TKIs) which target these receptors can increase the effectiveness of DNA damaging agents. However, these combinations have failed to produce the clinical results anticipated and one potential explanation is that the inhibition of EGFR and HER2 cell signalling pathways by TKIs is short lived, with cells able to switch to alternative mechanisms of signalling through HER3. The purpose of this study was to examine whether the duration of exposure to TKIs modulates the induction and repair of DNA damage produced by chemotherapy or IR and describes attempts to elucidate the role of HER2 in mediating resistance to chemotherapy. Experimental design: Two HER targeting TKIs, lapatinib and gefitinib were investigated. The effect of lapatinib in combination with cisplatin and doxorubicin on the inhibition of cell proliferation and the role of schedule were examined in drug combination assays. The influence of the duration of exposure to TKIs on the induction and repair of DNA lesions induced by cisplatin, IR, doxorubicin, etoposide and m-AMSA were investigated using the alkaline and neutral Comet assays and measurement of γH2AX and RAD51 foci. DNA expression arrays were used to identify the potential mechanisms through which HER2 produces resistance to cisplatin in cells transfected with HER2. Results: Lapatinib is able to synergistically inhibit cell proliferation in combination with cisplatin or doxorubicin in a schedule dependent manner. Duration of exposure to TKIs has no effect on the induction of DNA lesions by cisplatin or IR, but significantly reduces the production of DNA double strand breaks by doxorubicin, etoposide and m-AMSA in part through the down-regulation of the expression of topoisomerase IIα (Topo IIα), increasing resistance to these drugs. Conclusions: These results indicate the scheduling of small molecule TKIs targeted against EGFR and HER2 is important and continuous exposure to these drugs induces resistance to doxorubicin, etoposide and m-AMSA, through reduced expression of their target, Topo IIα. The importance of schedule should be considered when combining TKIs with chemotherapy in clinical practice.
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Kolli, Kaouther. « Rôle de la protéine FAK (Focal Adhésion Kinase) dans les mécanismes d'invasion cellulaire ». Thesis, Strasbourg, 2012. http://www.theses.fr/2012STRAJ003.

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Cette thèse traite du rôle de la protéine FAK (Focal Adhésion Kinase) dans les mécanismes d'invasion cellulaire
This thesis is about the role of the protein FAK (Focal Adhesion Kinase) in the cellular mechanisms of invasion
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Roos, Kelly. « The effect of sunitinib on neuroblastoma and glioblastoma cell growth ». University of the Western Cape, 2020. http://hdl.handle.net/11394/7952.

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Magister Scientiae (Medical Bioscience) - MSc(MBS)
Cancer is a global health catastrophe, with neuroblastoma, the most common solid childhood tumor, and glioblastoma, a deadly brain tumor, being aggressive and unresponsive to current treatment modalities. These tumors are known to utilize uncontrollable cell proliferative capabilities as a mechanism for tumor survival. Therefore, malignant cell growth can be mitigated by targeting the essential proteins that regulate cell growth, such as receptor tyrosine kinases (RTKs). Under normal physiological conditions, RTKs bind with varying affinity to mitogenic stimuli such as growth factors such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) which, in turn, leads to receptor phosphorylation and activation.
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Saleem, Mohammed Umer. « Preclinical evaluation of pharmacological strategies designed to enhance the activity of established and novel anti-cancer drugs : synopsis - evaluation of pharmacological strategies designed to modulate the Warburg effect, enhance the activity of tyrosine kinase inhibitors and novel analogues of Temozolomide ». Thesis, University of Bradford, 2014. http://hdl.handle.net/10454/13842.

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Whilst progress has been made in reducing mortality in some cancers, mortality rates remain high in many cancers and there is a need to develop novel therapeutic strategies. In this thesis, various pharmacological strategies designed to enhance the activity of existing therapeutic drugs were evaluated. Cancer cells are dependent upon aerobic glycolysis (the Warburg effect) and glutamine uptake. Using clinically approved tyrosine kinase inhibitors and Bortezomib, significant enhancement of chemosensitivity was observed when used in combination with inhibitors of lactate dehydrogenase (Gossypol) and pyruvate kinase dehydrogenase (Dichloroacetate). In contrast, depletion of glutamine from media had to be extensive in order to induce cell death and cell death only occurred after prolonged exposure to glutamine-deprived conditions. This suggests that glutamine depletion strategies alone are unlikely to be successful but may be useful in combination with other agents targeting glutamine addiction in cancer cells. Finally, Temozolomide (TMZ) is an important drug in the treatment of glioblastomas but its activity is reduced by resistance mechanisms including O6 methyl guanine methyltransferase (MGMT) and mismatch repair (MMR). This thesis has identified analogues of TMZ (EA02-45, EA02-59, EA02-64 and EA02-65) that are MGMT and MMR independent in terms of inducing cell kill in vitro. These compounds are promising leads for future development. In conclusion, this thesis has demonstrated that interfering with the metabolic phenotype of cancer can enhance the activity of existing drugs and identified novel analogues of TMZ that circumvent drug resistance mechanisms that hamper the efficacy of TMZ.
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Graf, Michael Georg Eduard. « Inhibition of ErbB2 by receptor tyrosine kinase inhibitors causes myofibrillarstructural damage without cell death in adult rat cardiomyocytes / ». [S.l.] : [s.n.], 2009. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.

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Skoglund, Karin. « Influence of CYP3A enzymes and ABC transporters on the activity of tyrosine kinase inhibitors in chronic myeloid leukemia ». Doctoral thesis, Linköpings universitet, Avdelningen för läkemedelsforskning, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-97427.

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The introduction of imatinib, a tyrosine kinase inhibitor (TKI), in the treatment of chronic myeloid leukemia (CML) was a major break-through and the first drug that was successfully designed to target the specific mechanism of a malignant disease. Imatinib still remains as the standard treatment of newly diagnosed CML patients although a second generation of TKIs has also been approved for first-line CML treatment. Most patients achieve a good therapeutic effect with imatinib, but some patients are resistant to the drug and are at greater risk of disease progression. In order to further improve CML treatment, a better understanding of the underlying reasons for variable responses to imatinib and the second generation TKIs is important. A number of potential determinants of imatinib response have been suggested, including interindividual variability in pharmacokinetics. Variations in drug metabolism and cellular transport might contribute to the large variations observed in imatinib plasma concentrations and might, therefore, affect the amount of drug that reaches target CML cells. Imatinib is primarily metabolized by the CYP3A hepatic enzymes that are known to be highly variable in activity between different individuals. Imatinib is also a substrate of the ABCB1 and ABCG2 efflux pumps that potentially regulate the elimination of imatinib from the plasma. The ABCB1 and ABCG2 genes are polymorphic and contain single nucleotide polymorphisms (SNPs) that might influence the transport capacity of these proteins. The primary aim of the present thesis was to investigate the influence of CYP3A metabolic activity and cellular transport mediated by genetic variants of ABCB1 and ABCG2 on the response to imatinib and the second generation TKIs used for CML therapy. In vivo CYP3A activity and plasma concentrations of imatinib and its pharmacologically active metabolite CGP74588 were analyzed in CML patients treated with imatinib. CYP3A phenotypes were correlated to plasma concentrations and imatinib outcome 12 months after initiation of treatment. The influence of ABC transport on TKI efficacy was evaluated in vitro by the transduction of genetic variants of ABCB1 and ABCG2 into the CML cell line K562. Functionality of the transport proteins was evaluated by measuring protein expression levels on the cell surface, the intracellular accumulation of TKIs, and the ability of ABCB1 and ABCG2 variants to protect cells from TKI cytotoxicity. We found that CYP3A metabolic activity does not influence the drug plasma concentrations or the therapeutic outcome of imatinib in CML patients. These findings indicate that even though imatinib is primarily metabolized by CYP3A this metabolic activity is not the rate-limiting step in imatinib elimination. CYP3A activity, therefore, is not a suitable predictive marker of imatinib outcome. The in vitro studies revealed that the ABCB1 variants investigated here do not alter the transport of imatinib, CGP74588, dasatinib, or nilotinib. In contrast, the ABCG2 SNPs 421C>A, 623T>C, 886G>C, and 1574T>G significantly impaired the cellular efflux of imatinib, CGP74588, dasatinib, and nilotinib and could possibly influence transport of these TKIs in vivo. It was also found that CGP74588 is by far a better substrate than imatinib for both ABCB1 and ABCG2, and this might have implications in patients with high levels of CYP3A activity. In conclusion, our studies show that ABCG2 SNPs might be important for prediction of imatinib outcome in vivo. On the other hand, CYP3A activity and the ABCB1 SNPs investigated in this study are not likely to be useful as predictors of imatinib outcome.
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Lou, Qiang 1962. « Identification of peptide substrates and development of pseudosubstrate-based peptide inhibitors for p60(C-SRC) protein tyrosine kinase ». Diss., The University of Arizona, 1996. http://hdl.handle.net/10150/282230.

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Protein tyrosine kinases (PTKs) mediate important signaling events associated with cellular growth, differentiation, and mitogenesis. The p60c-src protein is the first described cellular protein tyrosine kinase. Human p60c-src PTK has been implicated in the development of colon and breast cancer, and leukemia. However, the exact physiological role of p60c-src PTK or its physiological target proteins are not well known, and the mechanism by which the p60c-src PTK activity is regulated is not completely understood. Peptide substrates can be used to determine the substrate specificity and kinetic parameters, and therefore to provide important information for understanding of the physiological role and mechanism of action of this enzyme. Peptide substrates can also be used to develop pseudosubstrate-based peptide inhibitors for p60c-src PTK. Combinatorial peptide library methods have proven to be very powerful in identifying ligands for receptors and in discovering peptide substrates for protein kinases. In this dissertation, a "one-bead one-compound" combinatorial peptide library method was applied to identify peptide substrates for p60c-src PTK, the structure-activity relationship of the identified peptide substrates was studied, and the pseudosubstrate-based peptide inhibitors for p60c-src PTK were developed. Using the "one-bead one-compound" combinatorial peptide library method, a novel peptide, YIYGSFK, was identified as an efficient substrate for p60c-src PTK. The structure-activity relationship study was performed on over 70 analogs of YIYGSFK. It was determined that -Ile-Tyr- were the two critical residues required for activity. Based on this dipeptide motif a secondary library was synthesized (XIYXXXX, wherein X = all 19 eukaryotic amino acids except cysteine, I = isoleucine, Y = tyrosine) and screened with p60c-src PTK. One of the identified peptides, GIYWHHY, was found to be more efficient for p60c-src PTK than the parental compound, YIYGSFK. Several potent psedosubstrate based inhibitors were developed using GIYWHHY as a template. Some of the more potent inhibitors have branched structure indicating the enzyme active site can accommodate more than a linear motif. These data demonstrate that the "one-bead one-compound" combinatorial library method is a powerful tool to discover novel peptide substrates, and to develop pseudosubstrate-based peptide inhibitors for PTKs.
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Kamath, Jayesh Ramrao. « Development of pseudosubstrate-based peptide and peptidomimetic inhibitors of p60ᶜ⁻ˢʳᶜ protein tyrosine kinase using combinatorial chemistry technology ». Diss., The University of Arizona, 2000. http://hdl.handle.net/10150/289173.

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Several protein tyrosine kinases and the signaling pathways in which they participate have emerged as attractive targets for drug design. Specific and potent PTK inhibitors not only represent a new class of anticancer agents but may also be used as a powerful research tool to study the role of PTK-dependent cellular pathways in normal or tumor cell growth and to dissect the redundancy in signal transduction pathways. Dr. Lam's laboratory has previously reported identification of efficient and specific peptide substrates for p60ᶜ⁻ˢʳᶜ PTK using one-bead one-peptide combinatorial library method (Lam et al., 1995; Lou et al., 1996a and b). Based on the structure of these peptide substrates, I have identified and characterized potent and selective peptide inhibitors of p60ᶜ⁻ˢʳᶜ PTK. Some of the identified peptide inhibitors were used as a research tool in this dissertation to investigate the active site of the enzyme p60ᶜ⁻ˢʳᶜ PTK. In addition to potency and selectivity, a major criterion for a successful src inhibitor is its cell permeability as src is located inside the cell. Peptides are generally impermeable to cell membrane. A major accomplishment of this dissertation is development of cell permeable peptidomimetic inhibitors of p60ᶜ⁻ˢʳᶜ PTK based on the identified dipeptide motif --Ile-Tyr- (-I-Y-). This dissertation describes identification of tetrameric and trimeric peptidomimetic inhibitors using a combination of two combinatorial methods, the 'one-bead one-compound' combinatorial method and the 'iterative' combinatorial method. Some of the identified inhibitors seem to selectively affect transformed cells versus normal cells at lower concentrations. A lot of still needs to be done to optimize these inhibitors. However, the accomplished work in this dissertation proves the feasibility of the pseudosubstrate peptide-based approach for the development of cell permeable peptidomimetic inhibitors as anti-cancer therapeutic agents.
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Shor, Audrey Cathryn. « Src kinase inhibitors for the treatment of sarcomas : cellular and molecular mechanisms of action ». [Tampa, Fla] : University of South Florida, 2007. http://purl.fcla.edu/usf/dc/et/SFE0001906.

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Kurim, Sara. « Towards Novel Effective Combination Therapy for KRAS Mutant Non-Small Cell Lung Cancer ». Thesis, Université d'Ottawa / University of Ottawa, 2018. http://hdl.handle.net/10393/37444.

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Non-small-cell lung cancer (NSCLC) accounts for 80–85% of all lung cancers and is associated with significant mortality. As epidermal-growth-factor receptor (EGFR) is over-expressed in 80-90% of NSCLC, its inhibition via EGFR-Tyrosine Kinase inhibitors (EGFR-TKIs) is a main therapeutic strategy. However, patients with mutations in KRAS are resistant to EGFR-TKIs. A study in mutant KRAS-driven lung cancer in transgenic mice showed that tumor growth was dependent on the activity of focal adhesion kinase (FAK). Therefore, we hypothesized that KRAS-mutant NSCLC will be sensitive to FAK-TKIs and, given known FAK-EGFR cross-talk, FAK inhibition will sensitize KRAS-mutant NSCLC to EGFR-TKIs. We performed cell viability assays of WT versus mutant KRAS NSCLC cell lines following treatment with FAK-TKI alone or in combination with a clinically relevant EGFR-TKI. We found that KRAS-mutant cells were more sensitive to FAK-TKI than KRAS-WT NSCLC. In addition, we found that the combination treatment including FAK and EGFR TKIs resulted in reduced tumor cell viability as compared to treatment with either drug alone. This enhanced anti-tumor response could be due to FAK-TKI’s ability to down-regulate EGFR downstream targets. Our preliminary data suggests that in KRAS-mutant cells the drug combination appears to more effectively inhibit Akt activity than single drug treatment alone. This suggests an enhanced ability to impair cell survival following treatment with the drug combination. We also found that treatment with FAK TKI in KRAS mutant NSCLC cells resulted in increased activation of EGFR which was due in part to modulation of EGFR recycling and production of endogenous EGFR ligands. Thus, the combination of FAK- and EGFR-TKIs may be more effective in KRAS mutant NSCLC as treatment with EGFR-TKI overcomes the unexpected ‘side effect’ of treatment with FAK-TKI, namely activation of the EGFR pathway by this drug. The findings of our study are novel and have uncovered previously unrecognized outcomes of FAK inhibition on EGFR activity. Moreover, our data support the notion that the combination of FAK- and EGFR-TKIs could be an effective treatment for KRAS mutant NSCLC patients.
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