Relevant bibliographies by topics / Tyrosine Kinase Inhibitors (TKIs)

Academic literature on the topic 'Tyrosine Kinase Inhibitors (TKIs)'

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Published: 9 March 2023
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Journal articles on the topic "Tyrosine Kinase Inhibitors (TKIs)"

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Deininger, Michael. "Targeting Tyrosine Kinase Receptors." Blood 122, no. 21 (November 15, 2013): SCI—25—SCI—25. http://dx.doi.org/10.1182/blood.v122.21.sci-25.sci-25.

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Abstract Protein tyrosine kinases (PTKs) regulate cell growth and other key functions. Constitutive PTK activation by somatic mutations, overexpression, or abnormal upstream signaling is characteristic of many cancers, including hematologic malignancies, providing a rationale for therapeutically targeting PTKs with small molecules. Imatinib, an ATP-competitive inhibitor of BCR-ABL1, the PTK causal to chronic myeloid leukemia (CML), established a paradigm for tyrosine kinase inhibitors (TKIs) as cancer therapeutics. Although a relatively weak inhibitor, imatinib is effective in most patients with chronic phase CML (CML-CP), while responses are transient in blastic phase (CML-BP). Point mutations in the BCR-ABL1 kinase domain have emerged as a major mechanism of drug resistance. The more potent second-generation TKIs – dasatinib, nilotinib, and bosutinib – induce deeper and faster responses and are active against many imatinib-resistant mutants, with the exception of T315I in the gatekeeper position of the catalytic site. This problem was addressed with ponatinib, a third-generation TKI covering all single BCR-ABL1 mutants, including T315I. Ponatinib has excellent clinical activity in CML-CP patients who failed other TKIs, while responses in CML-BP are short-lived. Some patients fail ponatinib due to BCR-ABL1 compound mutations, suggesting even third-generation TKIs cannot completely prevent mutational escape by the disease-initiating kinase. Another unsolved problem is that TKIs fail to efficiently target CML stem cells, leading to recurrence of active leukemia upon discontinuation. Despite these shortcomings, TKIs have completely changed the face of CML. Unfortunately, repeating this success in other hematologic malignancies has been challenging, likely reflecting differences in disease biology as much as suboptimal design of early compounds. CML-CP represents one extreme of the spectrum, where a single genetic lesion is sufficient to produce the phenotype and the hierarchy of hematopoietic differentiation is maintained. The situation is different in acute myeloid leukemia (AML) with activating FLT3 mutations. Not only these AML cases have mutations in other genes, they typically acquire FLT3 mutations late during disease evolution, implying that the disease-initiating clone will be impervious to FLT3 inhibition. Progress has been made through successive development of more potent TKIs with improved pharmacology, leading to quizartinib. It is clear, however, that FLT3 inhibitors cannot be used as single agents if there is a curative intent and the same may be true for JAK2 inhibitors in myelofibrosis. The first approved JAK2 inhibitor, ruxolitinib, dramatically improves symptoms, but has yet to demonstrate a significant impact on the malignant clone and is certainly not curative. It remains to be seen whether this reflects the fact that JAK2 activation is not the disease–initiating event, lack of inhibitor specificity towards the mutant JAK2 kinase, or other undesirable off-target effects that may be overcome with improved drugs. A completely new chapter was opened with ibrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase (BTK), for the treatment of chronic lymphocytic leukemia (CLL). BTK is essential for signal transduction from the B-cell receptor (BCR). No activating mutations in BTK have been identified in lymphoma or CLL, but constitutive BCR signaling is critical to CLL cell survival in the microenvironment. Early studies show excellent clinical activity in patients with advanced CLL, although many responses are incomplete; much like the imatinib responses in late CML-CP. Ibrutinib may have a similarly profound effect upon CLL as imatinib on CML, but perhaps also similar limitations, such as the inability to eradicate residual leukemia; this of course needs to be tested in frontline studies. TKIs have had a significant albeit uneven impact upon treatment paradigms in hematologic malignancies. Future progress will involve optimizing compounds in terms of potency, selectivity, and pharmacokinetics. Allosteric inhibitors may add to the armamentarium. From the target perspective, it is likely that most activated kinase alleles have been discovered and the focus should shift to identification of disease-critical unmutated kinases. Lastly, identifying synthetically lethal inhibitor combinations will be critical to fully exploit the potential of TKI therapy. Disclosures: Deininger: BMS: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; ARIAD: Consultancy, Membership on an entity’s Board of Directors or advisory committees; NOVARTIS: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; CELGENE: Research Funding; GENZYME: Research Funding; INCYTE: Consultancy, Membership on an entity’s Board of Directors or advisory committees; GILEAD: Research Funding.
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Weatherald, Jason, Louise Bondeelle, Marie-Camille Chaumais, Christophe Guignabert, Laurent Savale, Xavier Jaïs, Olivier Sitbon, et al. "Pulmonary complications of Bcr-Abl tyrosine kinase inhibitors." European Respiratory Journal 56, no. 4 (June 11, 2020): 2000279. http://dx.doi.org/10.1183/13993003.00279-2020.

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Tyrosine kinase inhibitors (TKIs) targeting the Bcr-Abl oncoprotein revolutionised the treatment of chronic myelogenous leukaemia. Following the success of imatinib, second- and third-generation molecules were developed. Different profiles of kinase inhibition and off-target effects vary between TKIs, which leads to a broad spectrum of potential toxicities.Pulmonary complications are most frequently observed with dasatinib but all other Bcr-Abl TKIs have been implicated. Pleural effusions are the most frequent pulmonary complication of TKIs, usually associated with dasatinib and bosutinib. Pulmonary arterial hypertension is an uncommon but serious complication of dasatinib, which is often reversible upon discontinuation. Bosutinib and ponatinib have also been associated with pulmonary arterial hypertension, while imatinib has not. Rarely, interstitial lung disease has been associated with TKIs, predominantly with imatinib.Mechanistically, dasatinib affects maintenance of normal pulmonary endothelial integrity by generating mitochondrial oxidative stress, inducing endothelial apoptosis and impairing vascular permeability in a dose-dependent manner. The mechanisms underlying other TKI-related complications are largely unknown. Awareness and early diagnosis of the pulmonary complications of Bcr-Abl TKIs is essential given their seriousness, potential reversibility, and impact on future treatment options for the underlying chronic myelogenous leukaemia.
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Preda, Mariana, Andrei Seferian, Etienne-Marie Jutant, Marie-Camille Chaumais, Laurent Savale, Xavier Jaïs, Jason Weatherald, Olivier Sitbon, Marc Humbert, and David Montani. "Tyrosine Kinase Inhibitor–Induced Pulmonary Arterial Hypertension." Advances in Pulmonary Hypertension 17, no. 2 (January 1, 2018): 69–74. http://dx.doi.org/10.21693/1933-088x-17.2.69.

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The treatment of the malignant hematological diseases has been revolutionized by the use of tyrosine kinase inhibitors (TKI): for example, imatinib in patients with chronic myeloid leukemia. Dasatinib, a second-generation TKI, has been reported to induce severe pulmonary arterial hypertension (PAH). The mechanism of PAH development is presumed to be endothelial cell toxicity through the production of mitochondrial reactive oxygen species. There are other TKIs that are reported to cause PAH, such as: ponatinib, bosutinib, lapatinib, and lorlatinib. The management of PAH due to TKIs primarily involves stopping the TKI treatment, which can lead to clinical and hemodynamic normalization. A third of the patients who develop PAH can have persistent symptoms of dyspnea and right heart failure even after the interruption of the TKIs. For these patients, use of specific PAH treatment is indicated along with close follow-up. In rare cases, TKI-induced PAH can be fatal. Thus, early screening for PAH diagnosis and proper management is required.
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Mongre, Raj Kumar, Chandra Bhushan Mishra, Arvind Kumar Shukla, Amresh Prakash, Samil Jung, Md Ashraf-Uz-Zaman, and Myeong-Sok Lee. "Emerging Importance of Tyrosine Kinase Inhibitors against Cancer: Quo Vadis to Cure?" International Journal of Molecular Sciences 22, no. 21 (October 28, 2021): 11659. http://dx.doi.org/10.3390/ijms222111659.

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GLOBOCAN 2020 estimated more than 19.3 million new cases, and about 10 million patients were deceased from cancer in 2020. Clinical manifestations showed that several growth factor receptors consisting of transmembrane and cytoplasmic tyrosine kinase (TK) domains play a vital role in cancer progression. Receptor tyrosine kinases (RTKs) are crucial intermediaries of the several cellular pathways and carcinogenesis that directly affect the prognosis and survival of higher tumor grade patients. Tyrosine kinase inhibitors (TKIs) are efficacious drugs for targeted therapy of various cancers. Therefore, RTKs have become a promising therapeutic target to cure cancer. A recent report shows that TKIs are vital mediators of signal transduction and cancer cell proliferation, angiogenesis, and apoptosis. In this review, we discuss the structure and function of RTKs to explore their prime role in cancer therapy. Various TKIs have been developed to date that contribute a lot to treating several types of cancer. These TKI based anticancer drug molecules are also discussed in detail, incorporating their therapeutic efficacy, mechanism of action, and side effects. Additionally, this article focuses on TKIs which are running in the clinical trial and pre-clinical studies. Further, to gain insight into the pathophysiological mechanism of TKIs, we also reviewed the impact of RTK resistance on TKI clinical drugs along with their mechanistic acquired resistance in different cancer types.
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Ye, Lei, Libero Santarpia, and Robert F. Gagel. "The Evolving Field of Tyrosine Kinase Inhibitors in the Treatment of Endocrine Tumors." Endocrine Reviews 31, no. 4 (August 1, 2010): 578–99. http://dx.doi.org/10.1210/er.2009-0031.

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Abstract Activation of tyrosine kinase receptors (TKRs) and their related pathways has been associated with development of endocrine tumors. Compounds that target and inactivate the kinase function of these receptors, tyrosine kinase inhibitors (TKIs), are now being applied to the treatment of endocrine tumors. Recent clinical trials of TKIs in patients with advanced thyroid cancer, islet cell carcinoma, and carcinoid have shown promising preliminary results. Significant reductions in tumor size have been described in medullary and papillary thyroid carcinoma, although no complete responses have been reported. Case reports have described significant tumor volume reductions of malignant pheochromocytomas and paragangliomas. In addition, these compounds showed an initial tumoricidal or apoptotic response followed by long-term static effects on tumor growth. Despite the promising preliminary results, this class of therapeutic agents has a broad spectrum of adverse effects, mediated by inhibition of kinase activities in normal tissues. These adverse effects will have to be balanced with their benefit in clinical use. New strategies will have to be applied in clinical research to achieve optimal benefits. In this review, we will address the genetic alterations of TKRs, the rationale for utilizing TKIs for endocrine tumors, and current information on tumor and patient responses to specific TKIs. We will also discuss the adverse effects related to TKI treatment and the mechanisms involved. Finally, we will summarize the challenges associated with use of this class of compounds and potential solutions.
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Esteban-Villarrubia, Jorge, Juan José Soto-Castillo, Javier Pozas, María San Román-Gil, Inmaculada Orejana-Martín, Javier Torres-Jiménez, Alfredo Carrato, Teresa Alonso-Gordoa, and Javier Molina-Cerrillo. "Tyrosine Kinase Receptors in Oncology." International Journal of Molecular Sciences 21, no. 22 (November 12, 2020): 8529. http://dx.doi.org/10.3390/ijms21228529.

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Tyrosine kinase receptors (TKR) comprise more than 60 molecules that play an essential role in the molecular pathways, leading to cell survival and differentiation. Consequently, genetic alterations of TKRs may lead to tumorigenesis and, therefore, cancer development. The discovery and improvement of tyrosine kinase inhibitors (TKI) against TKRs have entailed an important step in the knowledge-expansion of tumor physiopathology as well as an improvement in the cancer treatment based on molecular alterations over many tumor types. The purpose of this review is to provide a comprehensive review of the different families of TKRs and their role in the expansion of tumor cells and how TKIs can stop these pathways to tumorigenesis, in combination or not with other therapies. The increasing growth of this landscape is driving us to strengthen the development of precision oncology with clinical trials based on molecular-based therapy over a histology-based one, with promising preliminary results.
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Abruzzese, Elisabetta, Malgorzata Monika Trawinska, Paolo De Fabritiis, and Alessio Pio Perrotti. "TYROSINE KINASE INHIBITORS AND PREGNANCY." Mediterranean Journal of Hematology and Infectious Diseases 6, no. 1 (April 7, 2014): e2014028. http://dx.doi.org/10.4084/mjhid.2014.028.

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The management of patients with chronic myeloid leukemia (CML) during pregnancy has became recently a matter of continuous debate. The introduction of the Tyrosine Kinase Inhibitors (TKIs) in clinical practice has dramatically changed the prognosis of CML patients. Patients diagnosed in chronic phase can reasonably expect many years of excellent disease control and good quality of life, as well as a normal life expectancy. This fact has come the necessity to address issues relating to fertility and pregnancy. Physicians are not infrequently being asked for advice regarding the need for, and or the appropriateness of, stopping treatment in order to conceive. In this report we will review the data published in terms of fertility, conception, pregnancy, pregnancy outcome and illness control for all the approved TKIs, as well as suggest how to manage a planned and/or unplanned pregnancy.
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Ergün Barış, Kaya, and Şener Yusuf Ziya. "Hypertensive toxicity of thyrosine kinase inhibitors; Friend or Foe?" Annals of Clinical Hypertension 5, no. 1 (January 12, 2021): 001–2. http://dx.doi.org/10.29328/journal.ach.1001025.

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Tyrosine kinase inhibitors (TKIs) are widely used in Oncology practice. Hypertension may develop during cancer treatment and TKIs are well known drugs that are associated with drug related hypertensive toxicity. TKI related hypertensive toxicity is not always the indicator of worse clinical outcomes and it may be the sign of treatment efficacy.
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Kong, Jee Hyun, Elliott F. Winton, Leonard T. Heffner, Manila Gaddh, Brittany Hill, Jessica Neely, Angela Hatcher, et al. "Outcomes of Chronic Phase Chronic Myeloid Leukemia after Treatment with Multiple Tyrosine Kinase Inhibitors." Journal of Clinical Medicine 9, no. 5 (May 20, 2020): 1542. http://dx.doi.org/10.3390/jcm9051542.

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We sought to evaluate the outcomes of chronic phase (CP) chronic myeloid leukemia (CML) in an era where five tyrosine kinase inhibitors (TKIs) are commercially available for the treatment of CML. Records of patients diagnosed with CP CML, treated with TKIs and referred to our center were reviewed. Between January 2005 and April 2016, 206 patients were followed for a median of 48.8 (1.4–190.1) months. A total of 76 (37%) patients received one TKI, 73 (35%) received two TKIs and 57 (28%) were exposed to >3 TKIs (3 TKIs, n = 33; 4 TKIs, n = 17; 5 TKIs, n = 7). Nineteen (9.2%) patients progressed to advanced phases of CML (accelerated phase, n = 6; myeloid blastic phase, n = 4; lymphoid blastic phase, n = 9). One third (n = 69) achieved complete molecular response (CMR) at first-line treatment. An additional 55 patients achieved CMR after second-line treatment. Twenty-five patients (12.1%) attempted TKI discontinuation and 14 (6.8%) stopped TKIs for a median of 6.3 months (range 1–53.4). The 10-year progression-free survival and overall survival (OS) rates were 81% and 87%, respectively. OS after 10-years, based on TKI exposure, was 100% (1 TKI), 82% (2 TKIs), 87% (3 TKIs), 75% (4 TKIs) and 55% (5 TKIs). The best OS was observed in patients tolerating and responding to first line TKI, but multiple TKIs led patients to gain treatment-free remission.
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Dimou, Maria, and Panagiotis Panagiotidis. "TYROSINE KINASE INHIBITORS AND INTERFERON." Mediterranean Journal of Hematology and Infectious Diseases 6, no. 1 (January 2, 2014): e2014006. http://dx.doi.org/10.4084/mjhid.2014.006.

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The use of interferon-a (INF) in chronic myeloid leukemia, when it started in the 80s, was considered as a breakthrough in the therapy of this disease; INF administered alone or in combination with aracytine was the standard choice for treatment for Chronic Myeloid Leukemia (CML) patients unfit for bone marrow transplantation. With the appearance of the first Tyrosine Kinase Inhibitor (TKI) (imatinib) and based on the results of the pivotal IRIS trial, imatinib monotherapy was the new treatment of choice for CML, according to the ELN recommendations. The possibility of combining INF with imatinib, for obtaining better therapeutic responses in CML patients has been already tested and reported. The current challenge is the combined use of second generation TKIs with pegylated –IFN, in order to minimize failures to therapy and increase the number of CML patients with deep molecular responses, who may be able to discontinue lifelong treatment.
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Dissertations / Theses on the topic "Tyrosine Kinase Inhibitors (TKIs)"

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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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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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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, and 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, and 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, and 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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Books on the topic "Tyrosine Kinase Inhibitors (TKIs)"

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Focosi, Daniele, ed. Resistance to Tyrosine Kinase Inhibitors. Cham: Springer International Publishing, 2016. http://dx.doi.org/10.1007/978-3-319-46091-8.

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D, Fabbro, and McCormick Frank 1950-, eds. Protein tyrosine kinases: From inhibitors to useful drugs. Totowa, N.J: Humana Press, 2006.

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Phosphoinositide 3-kinase in health and disease. Heidelberg: Springer Verlag, 2010.

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Rommel, Christian. Phosphoinositide 3-kinase in Health and Disease: Volume 2. Berlin, Heidelberg: Springer-Verlag Berlin Heidelberg, 2011.

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Matthews, David J. Targeting protein kinases for cancer therapy. Hoboken, N.J: John Wiley & Sons, 2009.

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E, Gerritsen Mary, ed. Targeting protein kinases for cancer therapy. Hoboken, N.J: John Wiley & Sons, 2010.

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Focosi, Daniele. Resistance to Tyrosine Kinase Inhibitors. Springer International Publishing AG, 2018.

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Focosi, Daniele. Resistance to Tyrosine Kinase Inhibitors. Springer, 2016.

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Focosi, Daniele. Resistance to Tyrosine Kinase Inhibitors. Springer, 2016.

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McCormick, Frank, and Doriano Fabbro. Protein Tyrosine Kinases: From Inhibitors to Useful Drugs. Humana Press, 2010.

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Book chapters on the topic "Tyrosine Kinase Inhibitors (TKIs)"

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Cakar, Burcu, and Erdem Göker. "Tyrosine Kinase Inhibitors." In Breast Disease, 617–31. Cham: Springer International Publishing, 2016. http://dx.doi.org/10.1007/978-3-319-26012-9_36.

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Cakar, Burcu, and Erdem Göker. "Tyrosine Kinase Inhibitors." In Breast Disease, 529–39. Cham: Springer International Publishing, 2019. http://dx.doi.org/10.1007/978-3-030-16792-9_35.

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Duhé, Roy J. "Tyrosine Kinase Inhibitors." In Encyclopedia of Cancer, 1–3. Berlin, Heidelberg: Springer Berlin Heidelberg, 2015. http://dx.doi.org/10.1007/978-3-642-27841-9_6080-2.

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Abad, Cybele Lara R., and Raymund R. Razonable. "Tyrosine-Kinase Inhibitors." In Infectious Complications in Biologic and Targeted Therapies, 273–92. Cham: Springer International Publishing, 2022. http://dx.doi.org/10.1007/978-3-031-11363-5_15.

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Duhé, Roy J. "Tyrosine Kinase Inhibitors." In Encyclopedia of Cancer, 4705–7. Berlin, Heidelberg: Springer Berlin Heidelberg, 2017. http://dx.doi.org/10.1007/978-3-662-46875-3_6080.

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Duhé, Roy J. "Tyrosine Kinase Inhibitors." In Encyclopedia of Cancer, 3822–24. Berlin, Heidelberg: Springer Berlin Heidelberg, 2011. http://dx.doi.org/10.1007/978-3-642-16483-5_6080.

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Latham, Antony M., Jayakanth Kankanala, and Sreenivasan Ponnambalam. "Receptor Tyrosine Kinase Inhibitors." In Encyclopedia of Cancer, 1–7. Berlin, Heidelberg: Springer Berlin Heidelberg, 2015. http://dx.doi.org/10.1007/978-3-642-27841-9_7196-1.

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Latham, Antony M., Jayakanth Kankanala, and Sreenivasan Ponnambalam. "Receptor Tyrosine Kinase Inhibitors." In Encyclopedia of Cancer, 3940–46. Berlin, Heidelberg: Springer Berlin Heidelberg, 2016. http://dx.doi.org/10.1007/978-3-662-46875-3_7196.

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Fushiki, Hiroshi, Yoshihiro Murakami, Sosuke Miyoshi, and Shintaro Nishimura. "PET Imaging for Tyrosine Kinase Inhibitor (TKI) Biodistribution in Mice." In Methods in Molecular Biology, 199–206. New York, NY: Springer New York, 2014. http://dx.doi.org/10.1007/978-1-4939-1661-0_15.

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Melosky, Barbara. "Cutaneous Reactions to Tyrosine Kinase Inhibitors." In Skin Diseases in the Immunocompromised, 107–20. London: Springer London, 2014. http://dx.doi.org/10.1007/978-1-4471-6479-1_10.

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Conference papers on the topic "Tyrosine Kinase Inhibitors (TKIs)"

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Yalcin, Huseyin, Hissa Al-Thani, and Samar Shurbaji. "Development and In Vivo Testing of Smart Nanoparticles for Enhanced Anti-Cancer Activity and Reduced Cardiotoxicity Associated with Tyrosine Kinase Inhibitors." In Qatar University Annual Research Forum & Exhibition. Qatar University Press, 2021. http://dx.doi.org/10.29117/quarfe.2021.0088.

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Tyrosine kinase inhibitors (TKIs) are new generation of anti-cancer drugs with very high efficiency against cancer cells. However, TKIs are associated with severe cardiotoxicity limiting their clinical benefits. One TKI that has been developed recently but not explored much is Ponatinib. The use of nanoparticles as a better therapeutic agent to deliver anti-cancer drugs and reduce their cardiotoxicity has been recently considered. In this study, PLGA-PEG-PLGA nanoparticles were synthesized to deliver Ponatinib while reducing its cardiotoxicity for treatment of chronic myeloid leukemia. Shape, size, surface charge and drug uptake ability of these nanoparticles were assessed using transmission electron microscopy (TEM), ZetaSIZER NANO and high-performance liquid chromatography (HPLC). Cardiotoxicity of Ponatinib, unloaded and loaded PLGA-PEG-PLGA nanoparticles were studied on zebrafish model through measuring the survival rate and cardiac function parameters, to optimize efficient drug concentrations in an in vivo setting. These particles were tested on zebrafish cancer xenograft model in which, K562 cell line, was transplanted into zebrafish embryos. We showed that, at an optimal concentration (0.0025mg/ml), Ponatinib loaded PLGA-PEG-PLGA particles are non-toxic/non-cardio-toxic and are very efficient against cancer growth and metastasis. Zebrafish is a good animal model for investigating the cardiotoxicity associated with the anti-cancer drugs such as TKIs, to determine the optimum concentration of smart nanoparticles with the least side effects and to generate xenograft model of several cancer types. Also, PLGA-PEG-PLGA NPs could be good candidate for CML treatment, but their cellular internalization should be enhanced. This could be achieved by coating and labeling the surface of PLGA-PEG-PLGA NPs with specific ligands that are unique to CML cells.
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Kapoor, Gurpreet Singh, Yi Zhan, Heather Fetting, and Donald M. O'Rourke. "Abstract LB-11: PTEN modulates EGFRvIII-induced SHP2 phosphorylation and translocation to affect glioblastoma sensitivity to tyrosine kinase inhibitors (TKIs)." In Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1538-7445.am2011-lb-11.

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Honeywell, Richard J., Sarina Hitzerd, Ietje Kathmann, Elisa Giovannetti, Henk Verheul, and Frits Peters. "Abstract 4425: Characterisation of cellular transport and accumulation of six clinically approved tyrosine kinase inhibitors (TKIs) in colon cancer cells." In Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.am2013-4425.

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Cascone, Tina, Matthew H. Herynk, Li Xu, Humam N. Kadara, Emer Hanrahan, You-Hong Fan, Babita Siagal, et al. "Abstract 376: Increased HGF is associated with resistance to VEGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC)." In Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-376.

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Zhao, Jane, Adriana Guerrero, Kevin Kelnar, Heidi J. Peltier, and Andreas G. Bader. "Abstract 4814: miRNA combination therapy:In vitroanticancer synergy between miR-34a mimic and next generation EGFR tyrosine kinase inhibitors (TKIs) in NSCLC." In Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.am2016-4814.

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Ward, Richard A., Ambra Bianco, Nicola Colclough, Darren Cross, Emanuela M. Cuomo, M. Raymond V. Finlay, Martina Fitzek, et al. "Abstract 4813: Comparative activity profiling of tyrosine kinase inhibitors (TKIs) against exon 20 insertions and the wild-type form of epidermal growth factor receptor (EGFR)." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-4813.

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Ward, Richard A., Ambra Bianco, Nicola Colclough, Darren Cross, Emanuela M. Cuomo, M. Raymond V. Finlay, Martina Fitzek, et al. "Abstract 4813: Comparative activity profiling of tyrosine kinase inhibitors (TKIs) against exon 20 insertions and the wild-type form of epidermal growth factor receptor (EGFR)." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.am2019-4813.

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Papayannidis, Cristina, Ilaria Iacobucci, Simona Soverini, Sabrina Colarossi, Alessandra Gnani, Annalisa Lonetti, Anna Ferrari, et al. "Abstract 1804: Efficacy and clinical outcome of Philadelphia (Ph) positive acute lymphoblastic leukemia (ALL) patients treated with second generation tyrosine kinase inhibitors (TKIs): The Bologna experience." In Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-1804.

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Fan, Ni, Yiyu Zou, Balazs Halmos, Roman Perez-Soler, and Haiying Cheng. "Abstract 4748: RICTOR signaling modulates the activity of EGFR tyrosine kinase inhibitors (TKI) inEGFR-mutated non-small cell lung cancer (NSCLC)." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-4748.

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Fan, Ni, Yiyu Zou, Balazs Halmos, Roman Perez-Soler, and Haiying Cheng. "Abstract 4748: RICTOR signaling modulates the activity of EGFR tyrosine kinase inhibitors (TKI) inEGFR-mutated non-small cell lung cancer (NSCLC)." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.am2019-4748.

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Reports on the topic "Tyrosine Kinase Inhibitors (TKIs)"

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Song, Yaowen, Shuiyu Lin, Jun Chen, Silu Ding, and Jun Dang. First-line treatment with TKI plus brain radiotherapy vs TKI alone in EGFR-mutated non-small-cell lung cancer with brain metastases: a systematic review and meta-analysis. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, January 2023. http://dx.doi.org/10.37766/inplasy2023.1.0013.

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Review question / Objective: It remains uncertain whether first-line treatment with upfront brain radiotherapy (RT) in combination with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is superior to EGFR-TKIs alone in EGFR-mutated non-small-cell lung cancer with newly diagnosed brain metastases (BMs). We performed a meta-analysis to address this issue. Condition being studied: Brain radiotherapy (RT) has been shown to damage the blood-brain barrier (BBB) and improve the concentration of EGFR-TKIs in the CSF. Additionally, RT can result in a reduction of EGFR-TKIs resistance. Therefore, EGFR-TKIs in combination with brain RT should be more effective than EGFR-TKIs alone theoretically. However, results from retrospective studies are inconsistent. There is the possibility that patients characteristics or brain RT technique affect the efficacy of treatments. To date, there is still no randomized controlled trials (RCTs) comparing the two treatment strategies.
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Miller, Tod. Peptide-Bassed Inhibitors of Neu Tyrosine Kinase. Fort Belvoir, VA: Defense Technical Information Center, June 1999. http://dx.doi.org/10.21236/ada375133.

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Miller, W. T. Peptide-Based Inhibitors of Neu Tyrosine Kinase. Fort Belvoir, VA: Defense Technical Information Center, December 2000. http://dx.doi.org/10.21236/ada392289.

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Rosen, Neal. Development of Targeted Ansamycins as Novel Antiestrogens and Tyrosine Kinase Inhibitors. Fort Belvoir, VA: Defense Technical Information Center, September 1998. http://dx.doi.org/10.21236/ada369205.

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Rosen, Neal. Development of Targeted Ansamycins as Noval Antiestrogens and Tyrosine Kinase Inhibitors. Fort Belvoir, VA: Defense Technical Information Center, September 2000. http://dx.doi.org/10.21236/ada413599.

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Tinker, Anna V., Neesha C. Dhani, Prafull Ghatage, Deanna McLeod, Vanessa Samouëlian, Stephen A. Welch, and Alon D. Altman. Immune Checkpoint Inhibitors in Pretreated Metastatic Endometrial Cancer. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, January 2023. http://dx.doi.org/10.37766/inplasy2023.1.0038.

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Review question / Objective: Efficacy and safety of immune checkpoint inhibitors alone or in combination with tyrosine kinase inhibitors in patients with pretreated advanced, persistent, or recurrent metastatic endometrial cancer. Condition being studied: Advanced, persistent, or recurrent metastatic endometrial cancer. Study designs to be included: Non-randomized studies of monotherapy in populations selected for relevant biomarkers such as MMR, microsatellite stability, and PD-L1 expression status and randomized trials of ICI combinations in unselected patients.
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Seidman, Andrew D. EgF Receptor Mabs and Chemotherapy/Characterization of Synergistic Interactions Between Cytotoxic Agents and Inhibitors of the Tyrosine Kinase Growth Factor Receptor Signalling Cascade. Fort Belvoir, VA: Defense Technical Information Center, October 1998. http://dx.doi.org/10.21236/ada378229.

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Yu, Yushuai, Jie Zhang, Kaiyan Huang, Yuxiang Lin, and Chuangui Song. The efficacy and safety of Tyrosine kinase inhibitors in HER-2 positive breast cancer with brain metastases: A systematic review and Meta-analysis. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, July 2021. http://dx.doi.org/10.37766/inplasy2021.7.0064.

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Carraway, Kermit L. A Novel Screen for Suppressors of Breast Tumor Cell Growth Using an Oriented Random Peptide Library Method to Identify Inhibitors of the ErbB2 Tyrosine Kinase. Fort Belvoir, VA: Defense Technical Information Center, June 1998. http://dx.doi.org/10.21236/ada350899.

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Zheng, Jiaxi, and Haihua Yang. Clinical Benefits of Immune Checkpoint Inhibitors and Predictive Value of Tumor Mutation Burden in Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, January 2022. http://dx.doi.org/10.37766/inplasy2022.1.0008.

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Review question / Objective: Is immunotherapy associated with beneficial clinical outcomes for hepatocellular carcinoma (HCC) and how can combination immunotherapy be deployed to produce the best benefit? Is tumor mutation burden (TMB) a predictive biomarker for immune‐checkpoint inhibitors? Condition being studied: To this date, about 50 single-arm clinical trials and several randomized control trials (RCTs) presented final or interim results of investigations on the efficacy of PD-1/PD-L1 inhibitors for advanced HCC. In the CheckMate 459, IMbrave 050, and ORIENT-32, immunotherapies were found to significantly improve progression-free survival (PFS) and overall survival (OS) compared with sorafenib (a tyrosine-kinase inhibitor, as standard systemic treatment) in patients with advanced hepatocellular carcinoma. However, these clinical trials were different on clinical phases, sample size, and response evaluation criteria, and inconsistent clinical outcomes were shown in several trials.
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