Journal articles on the topic 'Kinase inhibitor treatments'
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1
Gäbler, Karoline, Catherine Rolvering, Valérie Palissot, Guy J. Berchem, Iris Behrmann, and Claude Haan. "Combined Inhibition of Janus and Aurora Kinase Effectively Suppresses Proliferation of JAK2 V617F-expressing Cells." Blood 118, no. 21 (November 18, 2011): 2813. http://dx.doi.org/10.1182/blood.v118.21.2813.2813.
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Abstract Abstract 2813 Background: A somatic point mutation in the Janus kinase 2 gene (JAK2) leading to the expression of the JAK2 V617F mutant occurs with high frequency in myeloproliferative neoplasm (MPN) patients (>95 % in polycythemia vera (PV), >50 % in essential thrombocythemia (ET) and primary myelofibrosis (PMF)). It confers constitutive activity to the kinase and results in cytokine hypersensitivity and a proliferative advantage of hematopoietic progenitor cells. These findings suggest that inhibiting JAK2 V617F may be therapeutically beneficial. Several JAK2 inhibitors are currently in clinical trials for the treatment of MPN, and first results show clinical improvements for PMF patients. However, since approximately 50 % of ET and PMF patients do not carry an activating mutation in JAK2, we speculate that the inhibition of signaling proteins other than JAK2 or in combination with JAK2 inhibition could be beneficial for these patients. Methods: We characterized compounds from different chemical classes, which previously have been published to be JAK(2) inhibitors. These compounds were compared in several assays using primary CD34+ cells from PV patients positive for the JAK2 V617F mutation and/or the JAK2 V617F-bearing cell line HEL. We used (quantitative) Western blot detections, in vitro kinase assays, proliferation assays, cell size measurements, cell cycle analyses and colony forming cell (CFC) assays to analyze the efficacy of the different inhibitors. Moreover, the IC50 values of the compounds were determined. Results: In total 15 published JAK2 inhibitors have been characterized in detail. As monitored in an in vitro kinase assay and by Western blot detection of phosphorylated signaling proteins, several compounds previously described as JAK(2) inhibitors did not target JAK2 V617F. However, some compounds, which turned out not to inhibit JAKs, showed growth-inhibitory effects on JAK2 V617F-positive cells. Such compounds could be used in combination with a specific JAK inhibitor in order to achieve beneficial effects on suppression of cell proliferation and induction of apoptosis. We could demonstrate that the combined application of a JAK inhibitor together with an Aurora kinase inhibitor was most promising: application of both Janus and Aurora kinase inhibitors in proliferation assays and CFC assays demonstrated a more effective suppression of growth than achieved by respective single treatments. Interestingly, we observed in the CFC assay that a JAK2 inhibitor seems to preferentially suppress the growth of erythroid colonies, while an Aurora kinase inhibitor preferentially blocks myeloid colony growth. Conclusion: Here we present a comparative analysis and a detailed biochemical characterization of numerous compounds from different chemical classes, all supposed to be JAK(2) inhibitors. We confirmed JAK(2) inhibitory activity for several compounds but not for all. In addition, we identified some compounds, which effectively inhibited the proliferation of JAK2 V617F-bearing cells without targeting JAK2. Thus, combined inhibition of JAK2 and other kinases may represent a promising therapeutic strategy. In particular, we suggest that a combination of Janus and Aurora kinase inhibitors might be beneficial for the treatment of MPN patients. Disclosures: No relevant conflicts of interest to declare.
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Lin, Yipeng. "Kinase inhibitor therapies for Chronic lymphocytic leukaemia (CLL): SYK, BTK and PI3K inhibitors." Highlights in Science, Engineering and Technology 19 (November 17, 2022): 30–35. http://dx.doi.org/10.54097/hset.v19i.2691.
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Chronic lymphocytic leukaemia (CLL) is a prevalent tumor disease in developed countries, and related therapies have been designed. However, CLL is still incurable. Chemoimmunotherapy is effective in inhibiting the proliferation of CLL cells, but nonspecific treatment can affect the growth of other immune cells. Kinase inhibitors are considered to be effective treatments for CLL as their anti-proliferation effects, and currently, popular kinase inhibitor therapies include SYK, BTK, and PI3K inhibitor therapy. PI3K is characterized by high efficiency and low side effects compared with the other two kinase inhibitor therapies, for instance, idelalisib and duvelisib. This review compares the advantages of each kinase inhibitor therapy through relevant studies and concludes that duvelisib has significant advantages and promising prospects compared to other CLL drugs. Further research may focus on exploring the mechanism of the role of kinase inhibitors in CLL as well as the clinical trials of kinase inhibitors in CLL patients.
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Tokuyama, Michio, and Tomotaka Mabuchi. "New Treatment Addressing the Pathogenesis of Psoriasis." International Journal of Molecular Sciences 21, no. 20 (October 11, 2020): 7488. http://dx.doi.org/10.3390/ijms21207488.
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Psoriasis is an immune cell-mediated inflammatory skin disease. The interleukin (IL)23/IL17 axis plays an important role in the development of psoriasis. The effectiveness of biologic treatments such as tumor necrosis factor (TNF)α inhibitors (infliximab, adalimumab, certolizumab pegol), IL23 inhibitors (ustekinumab, guselkumab, tildrakizumab, risankizumab), and IL17 inhibitors (secukinumab, ixekizumab, brodalumab) have verified these findings. Immune-related cells such as dendritic cells (DCs) and macrophages, in addition to Toll-like receptors and cytokines such as interferon (IFN)α, TNFα, IFNɤ, IL12, IL22, IL23, and IL17, are related to the pathogenesis of psoriasis. Here, we first review new insights regarding the pathogenesis of psoriasis, as it relates to DCs, Langerhans cells, macrophages, the signal transducer and activator of transcription 3 pathway, and aryl hydrocarbon receptor in cutaneous vascular endothelial cells. Based on these findings, we summarize currently available oral treatments and biologics. Furthermore, we describe a new treatment option including Janus kinase inhibitor, tyrosine kinase 2 inhibitor, modulator of sphingosine 1-phosphate receptor 1, and Rho-associated kinase 2 inhibitor.
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Ahmadu, Augustine A., Claire Delehouzé, Anas Haruna, Lukman Mustapha, Bilqis A. Lawal, Aniefiok Udobre, Blandine Baratte, et al. "Betulin, a Newly Characterized Compound in Acacia auriculiformis Bark, Is a Multi-Target Protein Kinase Inhibitor." Molecules 26, no. 15 (July 29, 2021): 4599. http://dx.doi.org/10.3390/molecules26154599.
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The purpose of this work is to investigate the protein kinase inhibitory activity of constituents from Acacia auriculiformis stem bark. Column chromatography and NMR spectroscopy were used to purify and characterize betulin from an ethyl acetate soluble fraction of acacia bark. Betulin, a known inducer of apoptosis, was screened against a panel of 16 disease-related protein kinases. Betulin was shown to inhibit Abelson murine leukemia viral oncogene homolog 1 (ABL1) kinase, casein kinase 1ε (CK1ε), glycogen synthase kinase 3α/β (GSK-3 α/β), Janus kinase 3 (JAK3), NIMA Related Kinase 6 (NEK6), and vascular endothelial growth factor receptor 2 kinase (VEGFR2) with activities in the micromolar range for each. The effect of betulin on the cell viability of doxorubicin-resistant K562R chronic myelogenous leukemia cells was then verified to investigate its putative use as an anti-cancer compound. Betulin was shown to modulate the mitogen-activated protein (MAP) kinase pathway, with activity similar to that of imatinib mesylate, a known ABL1 kinase inhibitor. The interaction of betulin and ABL1 was studied by molecular docking, revealing an interaction of the inhibitor with the ABL1 ATP binding pocket. Together, these data demonstrate that betulin is a multi-target inhibitor of protein kinases, an activity that can contribute to the anticancer properties of the natural compound and to potential treatments for leukemia.
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Flis, Sylwia, Ewelina Bratek, Tomasz Chojnacki, Marlena Piskorek, and Tomasz Skorski. "Simultaneous Inhibition of BCR-ABL1 Tyrosine Kinase and PAK1/2 Serine/Threonine Kinase Exerts Synergistic Effect against Chronic Myeloid Leukemia Cells." Cancers 11, no. 10 (October 12, 2019): 1544. http://dx.doi.org/10.3390/cancers11101544.
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Tyrosine kinase inhibitors (TKIs) revolutionized the treatment of chronic myeloid leukemia in the chronic phase (CML-CP). However, it is unlikely that they can completely “cure” the disease. This might be because some subpopulations of CML-CP cells such as stem and progenitor cells are resistant to chemotherapy, even to the new generation of TKIs. Therefore, it is important to look for new methods of treatment to improve therapeutic outcomes. Previously, we have shown that class I p21-activated serine/threonine kinases (PAKs) remained active in TKI-naive and TKI-treated CML-CP leukemia stem and early progenitor cells. In this study, we aimed to determine if simultaneous inhibition of BCR-ABL1 oncogenic tyrosine kinase and PAK1/2 serine/threonine kinase exert better anti-CML effect than that of individual treatments. PAK1 was inhibited by small-molecule inhibitor IPA-3 (p21-activated kinase inhibitor III), PAK2 was downregulated by specific short hairpin RNA (shRNA), and BCR-ABL1 tyrosine kinase was inhibited by imatinib (IM). The studies were conducted by using (i) primary CML-CP stem/early progenitor cells and normal hematopoietic counterparts isolated from the bone marrow of newly diagnosed patients with CML-CP and from healthy donors, respectively, (ii) CML-blast phase cell lines (K562 and KCL-22), and (iii) from BCR-ABL1-transformed 32Dcl3 cell line. Herein, we show that inhibition of the activity of PAK1 and/or PAK2 enhanced the effect of IM against CML cells without affecting the normal cells. We observed that the combined use of IM with IPA-3 increased the inhibition of growth and apoptosis of leukemia cells. To evaluate the type of interaction between the two drugs, we performed median effect analysis. According to our results, the type and strength of drug interaction depend on the concentration of the drugs tested. Generally, combination of IM with IPA-3 at the 50% of the cell kill level (EC50) generated synergistic effect. Based on our results, we hypothesize that IM, a BCR-ABL1 tyrosine kinase inhibitor, combined with a PAK1/2 inhibitor facilitates eradication of CML-CP cells.
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Grisouard, Jean, Elisa Bouillet, Katharina Timper, Tanja Radimerski, Kaethi Dembinski, Daniel M. Frey, Ralph Peterli, et al. "Both inflammatory and classical lipolytic pathways are involved in lipopolysaccharide-induced lipolysis in human adipocytes." Innate Immunity 18, no. 1 (November 18, 2010): 25–34. http://dx.doi.org/10.1177/1753425910386632.
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High fat diet-induced endotoxaemia triggers low-grade inflammation and lipid release from adipose tissue. This study aims to unravel the cellular mechanisms leading to the lipopolysaccharide (LPS) effects in human adipocytes. Subcutaneous pre-adipocytes surgically isolated from patients were differentiated into mature adipocytes in vitro. Lipolysis was assessed by measurement of glycerol release and mRNA expression of pro-inflammatory cytokines were evaluated by real-time PCR. Treatment with LPS for 24 h induced a dose-dependent increase in interleukin (IL)-6 and IL-8 mRNA expression. At 1 µg/ml LPS, IL-6 and IL-8 were induced to 19.5 ± 1.8-fold and 662.7 ± 91.5-fold ( P < 0.01 vs basal), respectively. From 100 ng/ml to 1 µg/ml, LPS-induced lipolysis increased to a plateau of 3.1-fold above basal level ( P < 0.001 vs basal). Co-treatment with inhibitors of inhibitory kappa B kinase kinase beta (IKKβ) or NF-κB inhibited LPS-induced glycerol release. Co-treatment with the protein kinase A (PKA) inhibitor H-89, the lipase inhibitor orlistat or the hormone-sensitive lipase (HSL) inhibitor CAY10499 abolished the lipolytic effects of LPS. Co-treatment with the MAPK inhibitor, U0126 also reduced LPS-induced glycerol release. Inhibition of lipolysis by orlistat or CAY10499 reduced LPS-induced IL-6 and IL-8 mRNA expression. Induction of lipolysis by the synthetic catecholamine isoproterenol or the phosphodiesterase type III inhibitor milrinone did not alter basal IL-6 and IL-8 mRNA expression after 24 treatments whereas these compounds enhanced LPS-induced IL-6 and IL-8 mRNA expression. Both the inflammatory IKKβ/NF-κB pathway and the lipolytic PKA/HSL pathways mediate LPS-induced lipolysis. In turn, LPS-induced lipolysis reinforces the expression of pro-inflammatory cytokines and, thereby, triggers its own lipolytic activity.
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Okabe, Seiichi, Tetsuzo Tauchi, Seiichiro Katagiri, Yuko Tanaka, and Kazuma Ohyashiki. "Combining ABL1 Kinase Inhibitor, Imatinib and the Jak Kinase Inhibitor TG101348: A Potential Treatment for Residual BCR-ABL Positive Leukemia Cells." Blood 120, no. 21 (November 16, 2012): 3737. http://dx.doi.org/10.1182/blood.v120.21.3737.3737.
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Abstract Abstract 3737 ABL kinase inhibitor, imatinib is highly effective therapy against chronic myeloid leukemia (CML) patients and eliminates disease progression and transformation. However, imatinib is not curative for most CML patients. Residual CML cells are present in bone marrow microenvironment. Bone marrow microenvironment is a source of soluble factors and regulates the proliferation of leukemia cells. These leukemia cells are contained within a niche in the bone marrow and are often impervious to current treatments, thus maintaining their proliferative activity when the treatment is ceased, suggests that the new therapeutic strategies designed to override stroma-associated drug resistance are required to treat against Philadelphia (Ph)-positive leukemia patients. The hematopoietic cytokine receptor signaling is mediated by tyrosine kinases termed Janus kinases (Jaks) and downstream transcription factors, signal transducers and activators of transcription (STATs). Jak-STAT signaling is also activated in CML cells. One of the Jak kinase inhibitor, TG101348 (SAR302503) is an orally available inhibitor of Jak2 and developed for the treatment of patients with myeloproliferative diseases. Therefore, combination therapy using a BCR-ABL tyrosine kinase inhibitors and a Jak inhibitor, TG101348 may help prevent stroma-associated drug resistance and these approaches may be expected to improve the outcomes of CML patients. In this study, we investigated the ABL tyrosine kinase inhibitor, imatinib and TG101348 efficacy by using the BCR-ABL positive cell lines, K562 and primary CML samples when leukemic cells were protected by the feeder cell lines (HS-5 and S9). 72 hours treatment of imatinib exhibits cell growth inhibition and induced apoptosis against K562 cells in a dose dependent manner. However, the treatment of imatinib exhibits cell growth inhibition partially against K562 cells in the presence of HS-5 conditioned media. We found that the treatment of TG101348 did not exhibit cell growth inhibition against K562 cells directly, but the combination treatment with imatinib and TG101348 abrogated the protective effects of HS-5 conditioned media in K562 cells. We next investigated the intracellular signaling of imatinib and TG101348. Phosphorylation of BCR-ABL, Crk-L was not reduced after TG101348 treatment. However, phosphorylation of BCR-ABL, Crk-L was significantly reduced and increased apoptosis after combination treatment with imatinib and TG101348. We next investigated the efficacy between imatinib and TG101348 by using CD34 positive primary CML samples. The treatment of imatinib exhibits cell growth inhibition partially against CD34 positive CML samples in the presence of feeder cells. Combined treatment of CD34 positive primary samples with imatinib and TG101348 caused significantly more cytotoxicity and induced apoptosis. We also found that mitogen-activated protein kinase (MAPK) was also inhibited by imatinib and TG101348 treatment. We next investigated the intracellular signaling of imatinib and TG101348 by using the CD34 positive primary samples. Phosphorylation of BCR-ABL, Crk-L was significantly reduced and increased apoptosis after treatment with imatinib and TG101348. Moreover, combination of imatinib and TG101348 inhibited the colony growth of Ph-positive primary samples. We also investigated the TG101348 activity against feeder cell. Phosphorylation of STAT5 was reduced by TG101348 in a dose dependent manner. The cytokine production was analyzed by using cytokine array systems. The cytokine production such as granulocyte macrophage colony-stimulating factor (GM-CSF) from HS-5 was also reduced by TG101348 treatment. Data from this study suggested that administration of the imatinib and Jak inhibitor, TG101348 may be a powerful strategy against stroma-associated drug resistance of Ph-positive cells and enhance cytotoxic effects of imatinib in those residual CML cells. Disclosures: No relevant conflicts of interest to declare.
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Boland, Sonja, Véronique Bonvallot, Thierry Fournier, Armelle Baeza-Squiban, Michel Aubier, and Francelyne Marano. "Mechanisms of GM-CSF increase by diesel exhaust particles in human airway epithelial cells." American Journal of Physiology-Lung Cellular and Molecular Physiology 278, no. 1 (January 1, 2000): L25—L32. http://dx.doi.org/10.1152/ajplung.2000.278.1.l25.
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We have previously shown that exposure to diesel exhaust particles (DEPs) stimulates human airway epithelial cells to secrete the inflammatory cytokines interleukin-8, interleukin-1β, and granulocyte-macrophage colony-stimulating factor (GM-CSF) involved in allergic diseases. In the present paper, we studied the mechanisms underlying the increase in GM-CSF release elicited by DEPs using the human bronchial epithelial cell line 16HBE14o−. RT-PCR analysis has shown an increase in GM-CSF mRNA levels after DEP treatments. Comparison of the effects of DEPs, extracted DEPs, or extracts of DEPs has shown that the increase in GM-CSF release is mainly due to the adsorbed organic compounds and not to the metals present on the DEP surface because the metal chelator desferrioxamine had no inhibitory effect. Furthermore, radical scavengers inhibited the DEP-induced GM-CSF release, showing involvement of reactive oxygen species in this response. Moreover genistein, a tyrosine kinase inhibitor, abrogated the effects of DEPs on GM-CSF release, whereas protein kinase (PK) C, PKA, cyclooxygenase, or lipoxygenase inhibitors had no effect. PD-98059, an inhibitor of mitogen-activated protein kinase, diminished the effects of DEPs, whereas SB-203580, an inhibitor of p38 mitogen-activated protein kinase, had a lower effect, and DEPs did actually increase the active, phosphorylated form of the extracellular signal-regulated kinase as shown by Western blotting. In addition, cytochalasin D, which inhibits the phagocytosis of DEPs, reduced the increase in GM-CSF release after DEP treatment. Together, these data suggest that the increase in GM-CSF release is mainly due to the adsorbed organic compounds and that the effect of native DEPs requires endocytosis of the particles. Reactive oxygen species and tyrosine kinase(s) may be involved in the DEP-triggered signaling of the GM-CSF response.
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Osses, Nelson, and Enrique Brandan. "ECM is required for skeletal muscle differentiation independently of muscle regulatory factor expression." American Journal of Physiology-Cell Physiology 282, no. 2 (February 1, 2002): C383—C394. http://dx.doi.org/10.1152/ajpcell.00322.2001.
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Transcription of specific skeletal muscle genes requires the expression of the muscle regulatory factor myogenin. To assess the role of the extracellular matrix (ECM) in skeletal muscle differentiation, the specific inhibitors of proteoglycan synthesis, sodium chlorate and β-d-xyloside, were used. Treatment of cultured skeletal muscle cells with each inhibitor substantially abolished the expression of creatine kinase and α-dystroglycan. This inhibition was totally reversed by the addition of exogenous ECM. Myoblast treatment with each inhibitor affected the deposition and assembly of the ECM constituents glypican, fibronectin, and laminin. These treatments did not affect MyoD, MEF2A, and myogenin expression and nuclear localization. Differentiated myoblast treatment with RGDS peptides completely inhibited myogenesis without affecting the expression or nuclear localization of myogenin. Integrin-mediated signaling of focal adhesion kinase was partially inhibited by chlorate and β-d-xyloside, an effect reversed by the addition of exogenous ECM gel. These results suggested that the expression of myogenin is not sufficient to successfully drive skeletal muscle formation and that ECM is required to complete the skeletal muscle differentiation process.
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Bilodeau-Goeseels, Sylvie, Nora Magyara, and Coralie Collignon. "Characterization of the effects of metformin on porcine oocyte meiosis and on AMP-activated protein kinase activation in oocytes and cumulus cells." Zygote 22, no. 2 (April 12, 2013): 275–85. http://dx.doi.org/10.1017/s0967199413000075.
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SummaryThe adenosine monophosphate-activated protein kinase (AMPK) activators 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside (AICAR) and metformin (MET) inhibit resumption of meiosis in porcine cumulus-enclosed oocytes. The objective of this study was to characterize the inhibitory effect of MET on porcine oocyte meiosis by: (1) determining the effects of an AMPK inhibitor and of inhibitors of signalling pathways involved in MET-induced AMPK activation in other cell types on MET-mediated meiotic arrest in porcine cumulus-enclosed oocytes; (2) determining whether MET and AICAR treatments lead to increased activation of porcine oocyte and/or cumulus cell AMPK as measured by phosphorylation of its substrate acetyl-CoA carboxylase; and (3) determining the effects of inhibition of the AMPK kinase, Ca2+/calmodulin-dependent protein kinase kinase (CaMKK), and Ca2+ chelation on oocyte meiotic maturation and AMPK activation in porcine oocytes and cumulus cells. The AMPK inhibitor compound C (CC; 1 μM) did not reverse the inhibitory effect of AICAR (1 mM) and MET (2 mM) on porcine oocyte meiosis. Additionally, CC had a significant inhibitory effect on its own. eNOS, c-Src and PI-3 kinase pathway inhibitors did not reverse the effect of metformin on porcine oocyte meiosis. The level of acetyl-CoA carboxylase (ACC) phosphorylation in oocytes and cumulus cells did not change in response to culture in the presence of MET, AICAR, CC, the CaMKK inhibitor STO-609 or the Ca2+ chelator BAPTA-AM for 3 h, but STO-609 increased the percentage of porcine cumulus-enclosed oocytes (CEO) that remained at the germinal vesicle (GV) stage after 24 h of culture. These results indicate that the inhibitory effect of MET and AICAR on porcine oocyte meiosis was probably not mediated through activation of AMPK.
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George, Daniel J., Chung-Han Lee, and Daniel Heng. "New approaches to first-line treatment of advanced renal cell carcinoma." Therapeutic Advances in Medical Oncology 13 (January 2021): 175883592110347. http://dx.doi.org/10.1177/17588359211034708.
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The treatment of patients with renal cell carcinoma (RCC) is evolving rapidly, with promising new regimens being developed and approved for patients with advanced disease, particularly the combination of tyrosine kinase inhibitors with immune checkpoint inhibitors. Within the last 6 months, favorable first-line setting results for patients with clear cell RCC have been reported for the combination of cabozantinib plus nivolumab in the phase III CheckMate 9ER study, leading to its regulatory approval, and lenvatinib plus pembrolizumab in the phase III CLEAR study. Additional systemic first-line treatments for clear cell RCC include axitinib plus pembrolizumab, pazopanib, and sunitinib for favorable-risk patients and ipilimumab plus nivolumab, axitinib plus pembrolizumab, axitinib plus avelumab, and cabozantinib for intermediate- or poor-risk patients. In this review of novel approaches for first-line treatment of advanced RCC, we present an overview of current treatment strategies, the basis behind emerging treatment approaches, a summary of key results from the pivotal studies using tyrosine kinase inhibitor and immune checkpoint inhibitor combination therapy, novel treatments and strategies under development, and efforts for identifying biomarkers to guide treatment decisions.
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Giunti, Serena, Alessandro Antonelli, Andrea Amorosi, and Libero Santarpia. "Cellular Signaling Pathway Alterations and Potential Targeted Therapies for Medullary Thyroid Carcinoma." International Journal of Endocrinology 2013 (2013): 1–16. http://dx.doi.org/10.1155/2013/803171.
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Parafollicular C-cell-derived medullary thyroid cancer (MTC) comprises 3% to 4% of all thyroid cancers. While cytotoxic treatments have been shown to have limited efficacy, targeted molecular therapies that inhibit rearranged during transfection (RET) and other tyrosine kinase receptors that are mainly involved in angiogenesis have shown great promise in the treatment of metastatic or locally advanced MTC. Multi-tyrosine kinase inhibitors such as vandetanib, which is already approved for the treatment of progressive MTC, and cabozantinib have shown distinct advantages with regard to rates of disease response and control. However, these types of tyrosine kinase inhibitor compounds are able to concurrently block several types of targets, which limits the understanding of RET as a specific target. Moreover, important resistances to tyrosine kinase inhibitors can occur, which limit the long-term efficacy of these treatments. Deregulated cellular signaling pathways and genetic alterations in MTC, particularly the activation of the RAS/mammalian target of rapamycin (mTOR) cascades and RET crosstalk signaling, are now emerging as novel and potentially promising therapeutic treatments for aggressive MTC.
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Ng, Chin Lin, Alaeldin Abdalla, Greta Galambosi, Sinead Cuffe, Brendan Doyle, Brenda Griffin, and Donal J. Sexton. "Acute kidney Injury due to Alectinib, an Anaplastic Lymphoma Kinase inhibitor." Journal of Onco-Nephrology 5, no. 1 (January 27, 2021): 18–22. http://dx.doi.org/10.1177/2399369321989718.
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Introduction: The array of unintended effects of targeted oncological treatments is still being elucidated. Cognizance of these effects is important since they allow early identification and intervention. Methods: We report a case of progressive reduction in kidney function following the introduction of the oral second generation Anaplastic Lymphoma Kinase (ALK) Inhibitor: Alectinib for the treatment of metastatic non-small cell carcinoma of the lung (NSCLC). Kidney biopsy findings suggested that the predominant manifestation was acute tubular injury, which resolved with cessation of Alectinib therapy and did not recur with the introduction of the third generation ALK inhibitor Lorlatinib. Conclusions: This case report adds to the Onco-Nephrology literature in relation to the potential nephrotoxic effects of ALK inhibitors.
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Huynh, Thanh Kieu, Chien-Yi Ho, Chi-Hua Tsai, Chien-Kuo Wang, Yun-Ju Chen, Da-Tian Bau, Chih-Yen Tu, Tzong-Shiun Li, and Wei-Chien Huang. "Proteasome Inhibitors Suppress ErbB Family Expression through HSP90-Mediated Lysosomal Degradation." International Journal of Molecular Sciences 20, no. 19 (September 27, 2019): 4812. http://dx.doi.org/10.3390/ijms20194812.
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Although dual EGFR/HER2 tyrosine kinase inhibitor lapatinib has provided effective clinical benefits for HER2-positive breast cancer patients, acquired resistance to this drug remains a major concern. Thus, the development of alternative therapeutic strategies is urgently needed for patients who failed lapatinib treatment. Proteasome inhibitors have been reported to possess high anti-tumor activity to breast cancer cells. Therefore, this study aims to examine whether and how proteasome inhibitor bortezomib can overcome lapatinib resistance. Treatments with several proteasome inhibitors, including Bortezomib, MG132, and proteasome inhibitor I (PSI), as well as the viabilities of both HER2-positive breast cancer cell lines and their lapatinib-resistant clones, were inhibited. Importantly, the expressions of ErbB family were downregulated at both transcriptional and translational levels. Also, our results further indicated that proteasome inhibitors decreased ErbB family expression through lysosomal degradation pathway in a heat shock protein 90 (HSP90)-dependent manner. In this study, our data supported a potential approach to overcome the acquired resistance of HER2-overexpressing breast cancer patients to lapatinib using proteasome inhibitors.
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Mayrhofer, Johanna E., Florian Enzler, Andreas Feichtner, Ruth Röck, Jakob Fleischmann, Andrea Raffeiner, Philipp Tschaikner, et al. "Mutation-oriented profiling of autoinhibitory kinase conformations predicts RAF inhibitor efficacies." Proceedings of the National Academy of Sciences 117, no. 49 (November 23, 2020): 31105–13. http://dx.doi.org/10.1073/pnas.2012150117.
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Kinase-targeted therapies have the potential to improve the survival of patients with cancer. However, the cancer-specific spectrum of kinase alterations exhibits distinct functional properties and requires mutation-oriented drug treatments. Besides post-translational modifications and diverse intermolecular interactions of kinases, it is the distinct disease mutation which reshapes full-length kinase conformations, affecting their activity. Oncokinase mutation profiles differ between cancer types, as it was shown for BRAF in melanoma and non–small-cell lung cancers. Here, we present the target-oriented application of a kinase conformation (KinCon) reporter platform for live-cell measurements of autoinhibitory kinase activity states. The bioluminescence-based KinCon biosensor allows the tracking of conformation dynamics of full-length kinases in intact cells and real time. We show that the most frequent BRAF cancer mutations affect kinase conformations and thus the engagement and efficacy of V600E-specific BRAF inhibitors (BRAFi). We illustrate that the patient mutation harboring KinCon reporters display differences in the effectiveness of the three clinically approved BRAFi vemurafenib, encorafenib, and dabrafenib and the preclinical paradox breaker PLX8394. We confirmed KinCon-based drug efficacy predictions for BRAF mutations other than V600E in proliferation assays using patient-derived lung cancer cell lines and by analyzing downstream kinase signaling. The systematic implementation of such conformation reporters will allow to accelerate the decision process for the mutation-oriented RAF-kinase cancer therapy. Moreover, we illustrate that the presented kinase reporter concept can be extended to other kinases which harbor patient mutations. Overall, KinCon profiling provides additional mechanistic insights into full-length kinase functions by reporting protein–protein interaction (PPI)-dependent, mutation-specific, and drug-driven changes of kinase activity conformations.
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Scarpa, Mario, Shivani Kapoor, Danilo Perrotti, and Maria R. Baer. "Concurrent FLT3 Inhibitor and PP2A Activating Drug Treatment Induces Synergistic Cytotoxicity in Acute Myeloid Leukemia Cells with FLT3 Internal Tandem Duplication through Proteasomal Degradation of Pim-1 and c-Myc." Blood 132, Supplement 1 (November 29, 2018): 3951. http://dx.doi.org/10.1182/blood-2018-99-117609.
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Abstract Introduction: In 30% of acute myeloid leukemia (AML) patients, internal tandem duplication of fms-like tyrosine kinase 3 (FLT3-ITD) causes constitutive and aberrant FLT3 signaling, and these patients have short relapse-free and overall survival. FLT3 inhibitors have limited and transient efficacy, but their efficacy may be enhanced by combination with other drugs targeting FLT3 signaling. FLT3 activation also inhibits the tumor suppressor protein phosphatase 2A (PP2A). FLT3 inhibitors and PP2A-activating drugs have been shown to induce synergistic cytotoxicity in cells with FLT3-ITD. To address mechanisms underlying this effect, we studied effects of combination therapy on the oncogenic serine/threonine kinase Pim-1 and the transcription factor c-Myc, both of which are upregulated in cells with FLT3-ITD and are also PP2A substrates. Methods: Ba/F3-ITD and MV4-11 cells and AML patient blasts with FLT3-ITD were cultured with a FLT3 inhibitor, gilteritinib (ASP2215) or quizartinib (AC220), and/or the PP2A-activating drug fingolimod (FTY720) at pharmacologically relevant concentrations, or DMSO control. Drug combination effects were measured by combination index determined by the Chou-Talalay method using CompuSyn software. Apoptosis was measured by Annexin V/propidium iodide staining detected by flow cytometry. c-Myc and GAPDH control mRNA was measured by real-time polymerase chain reaction. Pim-1 kinase, c-Myc, phospho-c-MycSer62, phospho-c-MycThr58, phospho-STAT5Tyr694, STAT5, phospho-PP2ATyr307, PP2A, phospho-BADSer112 and BAD levels were measured by immunoblotting. Cycloheximide treatment was used to assess protein stability. Protein expression and stability were measured with and without the proteasome inhibitor MG-132. Pim-1 kinase was inhibited with the pan-Pim inhibitor AZD1208. Ba/F3-ITD cells were infected with pMX-Flag-K67M kinase-dead (KD) Pim-1 and empty pMX retroviral vectors and with pBABE-ER-cMYC and with empty pBABE-ER retroviral vectors. Results: Concurrent treatment with 15 nM gilteritinib or 1 nM quizartinib and FTY720 2 µM in cell lines and 4 µM in patient samples decreased growth and increased apoptosis of cells with FLT3-ITD, relative to single drug treatments, and produced synergistic cytotoxicity. FLT3 inhibition was confirmed by decrease in phospho-STAT5 and PP2A activation by decreased phospho-PP2A. Concurrent treatment decreased expression of both Pim-1 and c-Myc protein, but not c-Myc mRNA, in Ba/F3-ITD and MV4-11 cells and AML patient blasts with FLT3-ITD, relative to single drug treatments. Additionally, selective decrease in phospho-MycSer62, a stable c-Myc phosphoprotein that is dephosphorylated by PP2A, was seen, with persistence of phospho-c-MycThr58. FLT3 inhibitor and PP2A activator combination treatment was found to decrease stability of c-Myc and Pim-1 protein, in relation to single drugs. Moreover, pretreatment with the proteasome inhibitor MG-132 abrogated downregulation of Pim-1 and c-Myc protein expression and decrease in Pim-1 and c-Myc protein stability in Ba/F3-ITD cells treated with FLT3 inhibitor and PP2A activator. Pretreatment with the pan-Pim kinase inhibitor AZD1208, with Pim-1 inhibition confirmed by decreased phospho-BADS112 had no effect on c-Myc downregulation, and c-Myc was similarly downregulated in Pim-1 kinase-dead cells as in parental and empty-vector cells, demonstrating that combination treatment effects on c-Myc are not Pim-1 kinase-dependent. Additionally, FLT3 inhibitor and PP2A-activating drug combination induced apoptosis in 30% of cells with c-Myc overexpression, compared to 60% of parental and empty vector-infected cells. Finally, c-Myc overexpression did not abrogate Pim-1 downregulation by combination treatment. Conclusions: Concurrent FLT3 inhibitor and PP2A activating drug treatment induces synergistic cytotoxicity in AML cells with FLT3 internal tandem duplication through proteasomal degradation of Pim-1 and c-Myc, and effects on Pim-1 and c-Myc are independent. The data support in vivo testing of FLT3 inhibitor and PP2A-activating drug combinations and development of a clinical trial. Disclosures No relevant conflicts of interest to declare.
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Mattei, Jean Camille, Corinne Bouvier-Labit, Doriane Barets, Nicolas Macagno, Mathieu Chocry, Frédéric Chibon, Philippe Morando, et al. "Pan Aurora Kinase Inhibitor: A Promising Targeted-Therapy in Dedifferentiated Liposarcomas With Differential Efficiency Depending on Sarcoma Molecular Profile." Cancers 12, no. 3 (March 3, 2020): 583. http://dx.doi.org/10.3390/cancers12030583.
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Soft tissue sarcoma (STS) are rare and aggressive tumours. Their classification includes numerous histological subtypes of frequent poor prognosis. Liposarcomas (LPS) are the most frequent type among them, and the aggressiveness and deep localization of dedifferentiated LPS are linked to high levels of recurrence. Current treatments available today lead to five-year overall survival has remained stuck around 60–70% for the past three decades. Here, we highlight a correlation between Aurora kinasa A (AURKA) and AURKB mRNA overexpression and a low metastasis-free survival. AURKA and AURKB expression analysis at genomic and protein level on a 9-STS cell lines panel highlighted STS heterogeneity, especially in LPS subtype. AURKA and AURKB inhibition by RNAi and drug targeting with AMG 900, a pan Aurora Kinase inhibitor, in four LPS cell lines reduces cell survival and clonogenic proliferation, inducing apoptosis and polyploidy. When combined with doxorubicin, the standard treatment in STS, aurora kinases inhibitor can be considered as an enhancer of standard treatment or as an independent drug. Kinome analysis suggested its effect was linked to the inhibition of the MAP-kinase pathway, with differential drug resistance profiles depending on molecular characteristics of the tumor. Aurora Kinase inhibition by AMG 900 could be a promising therapy in STS.
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Nestal de Moraes, Gabriela, Paloma Silva Souza, Fernanda Casal de Faria Costas, Flavia Cunha Vasconcelos, Flaviana Ruade Souza Reis, and Raquel Ciuvalschi Maia. "The Interface between BCR-ABL-Dependent and -Independent Resistance Signaling Pathways in Chronic Myeloid Leukemia." Leukemia Research and Treatment 2012 (April 24, 2012): 1–19. http://dx.doi.org/10.1155/2012/671702.
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Chronic myeloid leukemia (CML) is a clonal hematopoietic disorder characterized by the presence of the Philadelphia chromosome which resulted from the reciprocal translocation between chromosomes 9 and 22. The pathogenesis of CML involves the constitutive activation of the BCR-ABL tyrosine kinase, which governs malignant disease by activating multiple signal transduction pathways. The BCR-ABL kinase inhibitor, imatinib, is the front-line treatment for CML, but the emergence of imatinib resistance and other tyrosine kinase inhibitors (TKIs) has called attention for additional resistance mechanisms and has led to the search for alternative drug treatments. In this paper, we discuss our current understanding of mechanisms, related or unrelated to BCR-ABL, which have been shown to account for chemoresistance and treatment failure. We focus on the potential role of the influx and efflux transporters, the inhibitor of apoptosis proteins, and transcription factor-mediated signals as feasible molecular targets to overcome the development of TKIs resistance in CML.
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Casado, Pedro, Edmund Wilkes, Marym M. Hadi, Vinothini Rajeeve, Farideh Miraki-Moud, Rebecca Pike, Ana Del Rio-Machin, et al. "Differentiation Status Revealed By Shotgun Phosphoproteomics Determines Sensitivity of Primary AML Cells to Kinase Inhibitors." Blood 128, no. 22 (December 2, 2016): 840. http://dx.doi.org/10.1182/blood.v128.22.840.840.
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Abstract Introduction Protein kinases play a key role in how cells respond and adapt to intra and extracellular stimuli. By the addition of phosphate groups to serine, threonine or tyrosine residues, these enzymes modify the activity and properties of the targeted proteins which in turn modulate biological processes like proliferation, differentiation and cell death. Kinase signalling pathways are deregulated in most cancer types including haematological malignancies. Indeed, the kinases FLt-3, c-Kit and JAK2 as well as the up-stream kinase signalling regulators KRAS and NRAS are among the most frequently mutated genes in acute myeloid leukaemia (AML). Consequently, protein kinases have attracted the attention of the pharmaceutical and biotechnology companies and inhibitors have been found for one fifth of human kinases. In the case of AML, midostaurin, a multi-kinase inhibitor that targets, among others, the tyrosine kinase Flt-3, has granted a breakthrough therapy designation by the FDA and several other kinase inhibitors are in clinical trials or under preclinical investigation. Molecular profiling of patient samples will play a pivotal role for the development and implementation of personalized therapies including those based on kinase inhibitors. We used a molecular profile generated by a phosphoproteomics approach to rationalize why some primary AML cells respond to treatment with different kinase inhibitors while others are resistant to the same treatments. Methods Label free phosphoproteomics based on trypsin digestion and TiO2 phosphoenrichment was used to quantify > 5,000 phosphorylation sites in mononuclear cells extracted from the peripheral blood of 36 AML patients. KSEA technology was applied to infer kinase activity from the phosphoproteomics data and DAVID software was used to determine gene ontology enrichments based on the genes that code for the proteins where the phosphorylation sites were detected. Guava EasyCyte Flow Cytometry was used to determine cell viability after the treatment of the same patient samples with different kinase inhibitors. Mass cytometry was used to measure the expression at the plasma membrane of 17 surface markers in 30 of the previously analysed AML primary samples. Results The FAB classification subdivide AML cases depending on cytomorphological features. We compared the phosphoproteomes of M1 and M4 classes that are associated with early and late states of differentiation. Based on the 150 phosphopeptides more significantly regulated between FAB-M1 and FAB-M4 groups, hierarchical clustering analysis was used to stratify AML patient samples into two subsets named M1-Like and M4-Like. Phosphoproteome reanalysis showed that the M4-Like set upregulated 1255 phosphopeptides and downregulated 446 when compared with the M1-Like set. The upregulated group comprised regulatory phosphorylation sites in several kinases including PAK1 and PCK delta. Kinase activity analysis using KSEA (Kinase Substrate Enrichment Analysis) also showed an increased activity of PAK, PKCδ and other kinases like P38 alpha in the M4-Like group. Interestingly, the PAK inhibitor PF03758309 reduced more efficiently the viability in M4-Like group than in the M1-Like group (average reduction after a 72h treatment with 1µM of 55.2% for M4-Like compared to 33.8% for M1-Like, p-value = 0.0078). This difference was not observed for other inhibitors such as those targeting CK2 or p38. CyTOF analysis showed that the M4-Like group upregulated the surface expression of several differentiation markers. Discussion Predicting the effectiveness of a drug for a particular patient is a major goal of personalized medicine. In the case of kinase inhibitors, responses may be influenced by several factors including the activity of the targeted kinase as well as the activity of other kinases that act in parallel pro-survival pathways. In this work, we have found that differentiation leads to a particular activation pattern of the signalling networks, a phenomenon that determines the response to signalling inhibitors. Conclusion We found phosphoproteomics signatures in primary AML that are associated with distinct haematopoietic differentiation stages. These signatures are in turn associated with how AML cells respond to kinase inhibitors. Disclosures Fitzgibbon: Epizyme: Research Funding; Gilead: Honoraria; Janssen: Honoraria; Celgene: Honoraria.
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Laface, Carmelo, Palma Fedele, Felicia Maria Maselli, Francesca Ambrogio, Caterina Foti, Pasquale Molinari, Michele Ammendola, Marco Lioce, and Girolamo Ranieri. "Targeted Therapy for Hepatocellular Carcinoma: Old and New Opportunities." Cancers 14, no. 16 (August 20, 2022): 4028. http://dx.doi.org/10.3390/cancers14164028.
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Hepatocellular carcinoma (HCC) is the most frequent primitive cancer of the liver, accounting for 90% of all recorded cases. HCC is the third most common cause of cancer-related death, with a 5-year survival rate of just 3%. In the advanced stages, systemic treatments allow doctors to obtain clinical benefits, although the prognosis remains very poor. In the past few decades, new molecular targeted therapies against receptor tyrosine kinases have been developed and clinically evaluated. Sorafenib was the first oral tyrosine kinase inhibitor (TKI) approved for the treatment of advanced HCC in 2007. Subsequently, other TKIs, including Cabozantinib, Regorafenib, Lenvatinib, and vascular endothelial growth factor receptor (VEGFR) inhibitors such as Ramucirumab and VEGF inhibitors such as Bevacizumab have been approved as first- or second-line treatments. More recently, the combination of immune checkpoint inhibitors and VEGF inhibitors (Atezolizumab plus Bevacizumab) have been analyzed and approved for the treatment of advanced HCC. On the basis of the poor prognoses and the meager benefits deriving from the available systemic therapies, research into new treatments is extremely necessary. In this review, we focus on the available systemic therapies for advanced HCC, with a look toward the future.
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Saylor, Philip J., and M. Dror Michaelson. "New Treatments for Renal Cell Carcinoma: Targeted Therapies." Journal of the National Comprehensive Cancer Network 7, no. 6 (June 2009): 645–56. http://dx.doi.org/10.6004/jnccn.2009.0045.
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Systemic treatment options for advanced renal cell carcinoma (RCC) have expanded considerably with the development of targeted therapies. Clear cell RCC commonly features mutation or inactivation of the von Hippel-Lindau gene and resultant overexpression of vascular endothelial growth factor (VEGF). The first drug to validate VEGF as a target in the treatment of clear cell RCC was the monoclonal antibody bevacizumab. Since then, anti-VEGF receptor therapy with multitargeted kinase inhibitors also has shown substantial efficacy. Sunitinib is now a standard first-line therapy for advanced disease and sorafenib is among the second-line treatment options. Other kinase inhibitors are in development. Mammalian target of rapamycin (mTOR) is a second validated therapeutic target as the mTOR inhibitor temsirolimus has been shown to prolong survival in first-line treatment of poor prognosis RCC of all histologies. Everolimus is an oral mTOR inhibitor and has been shown to prolong progression-free survival when used in second-line treatment. Non-clear cell and sarcomatoid RCC are both underrepresented in completed trials but are the subject of active research. Ongoing and planned studies will also evaluate the use of combinations of targeted agents, a strategy that is not advisable outside of clinical trials. Finally, postnephrectomy adjuvant treatment with targeted agents is not yet standard but is under investigation in phase III trials.
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Reimer, Raylene A. "Meat hydrolysate and essential amino acid-induced glucagon-like peptide-1 secretion, in the human NCI-H716 enteroendocrine cell line, is regulated by extracellular signal-regulated kinase1/2 and p38 mitogen-activated protein kinases." Journal of Endocrinology 191, no. 1 (October 2006): 159–70. http://dx.doi.org/10.1677/joe.1.06557.
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Glucagon-like peptide-1 (GLP-1) is a potent insulin secretagogue released from L-cells in the intestine. Meat hydrolysate (MH) is a powerful activator of GLP-1 secretion in the human enteroendocrine NCI-H716 cell line, but the mechanisms involved in nutrient-stimulated GLP-1 secretion are poorly understood. The objective of this study was to characterize the intracellular signalling pathways regulating MH- and amino acid-induced GLP-1 secretion. Individually, the pharmacological inhibitors, SB203580 (inhibitor of p38 mitogen-activated protein kinase (MAPK)), wortmannin (inhibitor of phosphatidyl inositol 3-kinase) and U0126 (inhibitor of mitogen activated or extracellular signal-regulated protein kinase (MEK1/2) upstream of extracellular signal-regulated kinase (ERK)1/2) all inhibited MH-induced GLP-1 secretion. Further examination of the MAPK pathway showed that MH increased the phosphorylation of ERK1/2, but not p38 or c-Jun N-terminal kinase over 2–15 min. Incubation with SB203580 resulted in a decrease in phosphorylated p38 MAPK and a concomitant increase in the phosphorylation of ERK1/2. Phosphorylation of ERK1/2 was augmented by co-incubation of MH with SB203580. Inhibitors of protein kinase A and protein kinase C did not inhibit MH-induced GLP-1 secretion. In contrast to non-essential amino acids, essential amino acids (EAAs) increased GLP-1 secretion and similar to MH, activated ERK1/2. However, they also activated p38-suggesting type of protein may affect GLP-1 secretion. In conclusion, there appears to be a crosstalk between p38 and ERK1/2 MAPK in the human enteroendocrine cell with the activation of ERK1/2 common to both MH and EAA. Understanding the cellular pathways involved in nutrient-stimulated GLP-1 secretion has important implications for the design of new treatments aimed at increasing endogenous GLP-1 release in type-2 diabetes and obesity.
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Finan, P. M., and M. J. Thomas. "PI 3-kinase inhibition: a therapeutic target for respiratory disease." Biochemical Society Transactions 32, no. 2 (April 1, 2004): 378–82. http://dx.doi.org/10.1042/bst0320378.
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Asthma and COPD (chronic obstructive pulmonary disease) are a growing major health burden, which, despite improvements in disease management, still require new effective treatments. As our understanding of the cellular and molecular processes which govern respiratory diseases improves, the range of potential therapeutic targets increase. PI 3-kinases (phosphoinositide 3-kinases) are a family of closely related enzymes, which play pivotal roles in a diverse array of cellular mechanisms. In the present paper, we review the evidence for PI 3-kinase involvement in various cellular processes underlying asthma and COPD generated through inhibitor studies and gene-targeting approaches, and discuss the prospects for PI 3-kinase inhibition as a future therapeutic strategy for the treatment of respiratory disease.
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Gray, Mike J., Gloria Wangrong YangKolodji, and Debu Tripathy. "Co-targeting PI3K and ras pathways in trastuzumab resistance." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e13515-e13515. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e13515.
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e13515 Background: HER2+ breast cancers (BC) account for 20–25% of invasive BC and are associated with an aggressive phenotype and poor patient outcome. The development of trastuzumab and other HER2-targeted therapy dramatically improved outcomes for HER2-positive BC, but most patients with advanced HER2+ BC will eventually become resistant to treatment, underlying the importance of developing alternative or combination treatments. Alterations in the PI3K/mTOR/Akt pathways are cited as contributors to the development of trastuzumab resistance, however targeting these kinases as single agents has yielded less than expected clinical results. This suggests that combinational treatment with other kinase pathway inhibitors may be required, including those targeting the Ras/MAPK pathway, which is typically not mutationally activated in breast cancer. Methods: Trastuzumab resistant HER2+ BC cell lines were subjected to dose responses with the mTOR inhibitor everolimus or the AKT inhibitor MK-2206 alone or in combination with the MEK 1/2 inhibitor GSK212 and changes in EC50s determined by MTT assay. Western blot analysis was performed to assess changes in the mTOR/AKT/ MAPK pathways or apoptotic regulators accompanying single or combination treatments. Results: In 4 of 5 trastuzumab-resistant HER2+ BC cell lines, each lacking activating mutations in the Ras/Raf pathway, combination treatment with everolimus or MK-2206 with GSK212 had significantly greater efficacy than by either inhibitor alone. Furthermore, combinational treatment targeting the mTOR and AKT pathways showed only an additive effect, and was much less effective than targeting both the MEK and PI3K pathways. Western analysis showed that AKT and mTOR inhibition caused a transient increase in ERK 1/2 activity in sensitive cell lines, suggesting that treatment by mTOR or AKT inhibitors activated critical survival pathways in the MAPK signaling that were blocked by GSK212. Conclusions: Treatment with mTOR or AKT inhibitors in combination with MEK inhibitors can act in a synergistic manner with greater efficacy than each inhibitor alone. Moreover, ERK 1/2 activity may serve as a predictive biomarker in trastuzumab-refractory patients treated with mTOR/MEK or AKT/MEK doublet therapy.
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Gild, Matti L., Iñigo Landa, Mabel Ryder, Ronald A. Ghossein, Jeffrey A. Knauf, and James A. Fagin. "Targeting mTOR in RET mutant medullary and differentiated thyroid cancer cells." Endocrine-Related Cancer 20, no. 5 (July 4, 2013): 659–67. http://dx.doi.org/10.1530/erc-13-0085.
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Inhibitors of RET, a tyrosine kinase receptor encoded by a gene that is frequently mutated in medullary thyroid cancer, have emerged as promising novel therapies for the disease. Rapalogs and other mammalian target of rapamycin (mTOR) inhibitors are effective agents in patients with gastroenteropancreatic neuroendocrine tumors, which share lineage properties with medullary thyroid carcinomas. The objective of this study was to investigate the contribution of mTOR activity to RET-induced signaling and cell growth and to establish whether growth suppression is enhanced by co-targeting RET and mTOR kinase activities. Treatment of the RET mutant cell lines TT, TPC-1, and MZ-CRC-1 with AST487, a RET kinase inhibitor, suppressed growth and showed profound and sustained inhibition of mTOR signaling, which was recapitulated by siRNA-mediated RET knockdown. Inhibition of mTOR with INK128, a dual mTORC1 and mTORC2 kinase inhibitor, also resulted in marked growth suppression to levels similar to those seen with RET blockade. Moreover, combined treatment with AST487 and INK128 at low concentrations suppressed growth and induced apoptosis. These data establish mTOR as a key mediator of RET-mediated cell growth in thyroid cancer cells and provide a rationale for combinatorial treatments in thyroid cancers with oncogenic RET mutations.
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Wang, Minmin, Tianyu Wang, Xiangyu Zhang, Xiaoxing Wu, and Sheng Jiang. "Cyclin-dependent kinase 7 inhibitors in cancer therapy." Future Medicinal Chemistry 12, no. 9 (May 2020): 813–33. http://dx.doi.org/10.4155/fmc-2019-0334.
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Cyclin-dependent kinase 7 (CDK7) plays crucial roles in the regulation of cell cycle and transcription that are tightly associated with cancer development and metastasis. The recent identification of the first covalent inhibitor which possesses high specificity against CDK7 prompts intense studies on designing highly selective CDK7 inhibitors and exploring their applications in cancer treatments. This review summarizes the latest biological studies on CDK7 and reviews the development of CDK7 inhibitors in preclinical and clinical evaluations, along with the prospects and potential challenges in this research area. CDK7 is an attractive anticancer target, and the discovery and development of CDK7 inhibitors has received much attention.
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Wierda, William G., and Francesco Paolo Tambaro. "How I manage CLL with venetoclax-based treatments." Blood 135, no. 17 (April 23, 2020): 1421–27. http://dx.doi.org/10.1182/blood.2019002841.
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Abstract Targeted therapies for chronic lymphocytic leukemia (CLL) include venetoclax, the oral inhibitor of B-cell lymphoma-2, and inhibitors of kinases in the B-cell receptor signaling pathway, like Bruton tyrosine kinase and phosphatidylinositol 3 kinase. Randomized clinical trials clearly demonstrated improved progression-free survival with targeted therapy over chemoimmunotherapy in first-line and treatment of relapsed/refractory CLL. Comparative trials of venetoclax-based vs other targeted therapies have not been conducted. Differentiating features and considerations with targeted therapies include goals of treatment and therapeutic approach as well as side effect and toxicity profiles. With targeted therapy options for first-line and relapsed CLL, it is ever more important to develop sound rationale and strategy for selecting first-line and treatment of relapsed disease and for long-term management of the disease, including therapeutic sequencing. Fixed-duration therapy with a treatment-free remission is a particularly appealing prospect, since it avoids continuous exposure to treatment and potential for toxicity. We discuss rationale and practical application of venetoclax in first-line and treatment of relapsed and refractory CLL. Venetoclax is highly active at achieving deep remission for most treated patients with CLL, including those with high-risk disease such as del(17p) CLL.
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dos Santos, Tabata M., Renato F. Righetti, Bianca G. Rezende, Elaine C. Campos, Leandro do N. Camargo, Beatriz M. Saraiva-Romanholo, Silvia Fukuzaki, et al. "Effect of anti-IL17 and/or Rho-kinase inhibitor treatments on vascular remodeling induced by chronic allergic pulmonary inflammation." Therapeutic Advances in Respiratory Disease 14 (January 2020): 175346662096266. http://dx.doi.org/10.1177/1753466620962665.
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Background and aims: Expansion and morphological dysregulation of the bronchial vascular network occurs in asthmatic airways. Interleukin (IL) -17 and Rho-kinase (ROCK) are known to act in inflammation control and remodeling. Modulation of Rho-kinase proteins and IL-17 may be a promising approach for the treatment of asthma through the control of angiogenesis. Our objective was to analyze the effects of treatment with anti-IL17 and/or Rho-kinase inhibitor on vascular changes in mice with chronic allergic pulmonary inflammation. Methods: Sixty-four BALB/c mice, with pulmonary inflammation induced by ovalbumin were treated with anti-IL17A (7.5/µg per dose, intraperitoneal) and/or Rho-kinase inhibitor (Y-27632-10 mg/kg, intranasal), 1 h before each ovalbumin challenge (22, 24, 26, and 28/days). Control animals were made to inhale saline. At the end of the protocol, lungs were removed, and morphometric analysis was performed to quantify vascular inflammatory, remodeling, and oxidative stress responses. Results: Anti-IL17 or Rho-kinase inhibitor reduced the number of CD4+, CD8+, dendritic cells, IL-4, IL-5, IL-6, IL-10, IL-13, IL-17, Rho-kinase 1 and 2, transforming growth factor (TGF-β), vascular endothelial growth factor (VEGF), nuclear factor (NF)-KappaB, iNOS, metalloproteinase (MMP)-9, MMP-12, metalloproteinase inhibitor-1 (TIMP-1), FOXP-3, signal transducer and activator of transcription 1 (STAT1) and phospho-STAT1-positive cells, and actin, endothelin-1, isoprostane, biglycan, decorin, fibronectin and the collagen fibers volume fraction compared with the ovalbumin group ( p < 0.05). The combination treatment, when compared with anti-IL17, resulted in potentiation of decrease in the number of IL1β- and dendritic cells-positive cells. When we compared the OVA-RHO inhibitor-anti-IL17 with OVA-RHO inhibitor we found a reduction in the number of CD8+ and IL-17, TGF-β, and phospho-STAT1-positive cells and endothelin-1 in the vessels ( p < 0.05). There was an attenuation in the number of ROCK 2-positive cells in the group with the combined treatment when compared with anti-IL17 or Rho-kinase inhibitor-treated groups ( p < 0.05). Conclusion: We observed no difference in angiogenesis after treatment with Rho-kinase inhibitor and anti-IL17. Although the treatments did not show differences in angiogenesis, they showed differences in the markers involved in the angiogenesis process contributing to inflammation control and vascular remodeling. The reviews of this paper are available via the supplemental material section.
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Khan, Zahra, Izabela Stasik, and Joseph Hayes. "Computer-aided Design of Novel CDK5 Inhibitors; Towards New Treatments of Glioblastoma." Neuro-Oncology 24, Supplement_4 (October 1, 2022): iv8. http://dx.doi.org/10.1093/neuonc/noac200.035.
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Abstract AIMS Design and statistically optimize an in silico screening protocol; apply the screening protocol to a compound database; in vitro validation of selected inhibitors (isolated CDK5 enzyme binding assay). METHOD Two large compound databases, ZINC15 and Analyticon Discovery, were used to screen for potential CDK5 ATP-binding site inhibitors. They were first filtered using a generated pharmacophore model and then virtually screened using Glide SP docking with a solved CDK5-p25 structure (PDB: 3O0G). The selected candidates were validated using enzyme binding assays to determine their inhibitory activity on CDK5, as well as against a panel of kinases. RESULTS Over 17,000 compounds were screened during molecular docking studies and of these, ~11,600 compounds returned which are predicted to bind to CDK5. The top 10% of docked compounds were analysed and 30 candidates were selected for single concentration screening at 50 µM concentrations. The 9 most potent compounds were selected for IC50 determinations and revealed 6 compounds with IC50 <10 µM. The selected novel compounds were also screened against a panel of kinases (CDK2, CDK5, CDK9, GSK-3β) with varying selective profiles observed. CONCLUSION Low micromolar potent compounds have been identified through in silico screening and validated in using in vitro binding assays. One flavonoid compound in particular, cirsiliol (IC50 = 5.90 µM), displayed best selectivity towards CDK5, a challenge in kinase inhibitor design. The identified compounds will now pass to cellular studies to determine their effect on Glioblastoma cell lines.
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Lin, You-Zhe, Yi-Chun Shen, Wan-Rong Wu, Wei-Jan Wang, Yuan-Liang Wang, Chen-Yuan Lin, Mien-Chie Hung, and Shao-Chun Wang. "Imatinib (STI571) Inhibits the Expression of Angiotensin-Converting Enzyme 2 and Cell Entry of the SARS-CoV-2-Derived Pseudotyped Viral Particles." International Journal of Molecular Sciences 22, no. 13 (June 28, 2021): 6938. http://dx.doi.org/10.3390/ijms22136938.
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A group of clinically approved cancer therapeutic tyrosine kinase inhibitors was screened to test their effects on the expression of angiotensin-converting enzyme 2 (ACE2), the cell surface receptor for SARS-CoV-2. Here, we show that the receptor tyrosine kinase inhibitor imatinib (also known as STI571, Gleevec) can inhibit the expression of the endogenous ACE2 gene at both the transcript and protein levels. Treatment with imatinib resulted in inhibition of cell entry of the viral pseudoparticles (Vpps) in cell culture. In FVB mice orally fed imatinib, tissue expression of ACE2 was reduced, specifically in the lungs and renal tubules, but not in the parenchyma of other organs such as the heart and intestine. Our finding suggests that receptor tyrosine kinases play a role in COVID-19 infection and can be therapeutic targets with combined treatments of the best conventional care of COVID-19.
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Koomoa, Dana-Lynn T., Mark W. Musch, Ainsley Vaz MacLean, and Leon Goldstein. "Volume-activated trimethylamine oxide efflux in red blood cells of spiny dogfish (Squalus acanthias)." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 281, no. 3 (September 1, 2001): R803—R810. http://dx.doi.org/10.1152/ajpregu.2001.281.3.r803.
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The aims of this study were to determine the pathway of swelling-activated trimethylamine oxide (TMAO) efflux and its regulation in spiny dogfish ( Squalus acanthias) red blood cells and compare the characteristics of this efflux pathway with the volume-activated osmolyte (taurine) channel present in erythrocytes of fishes. The characteristics of the TMAO efflux pathway were similar to those of the taurine efflux pathway. The swelling-activated effluxes of both TMAO and taurine were significantly inhibited by known anion transport inhibitors (DIDS and niflumic acid) and by the general channel inhibitor quinine. Volume expansion by hypotonicity, ethylene glycol, and diethyl urea activated both TMAO and taurine effluxes similarly. Volume expansion by hypotonicity, ethylene glycol, and diethyl urea also stimulated the activity of tyrosine kinases p72syk and p56lyn, although the stimulations by the latter two treatments were less than by hypotonicity. The volume activations of both TMAO and taurine effluxes were inhibited by tyrosine kinase inhibitors, suggesting that activation of tyrosine kinases may play a role in activating the osmolyte effluxes. These results indicate that the volume-activated TMAO efflux occurs via the organic osmolyte (taurine) channel and may be regulated by the volume activation of tyrosine kinases.
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Kiss, Z., and E. Deli. "Regulation of phospholipase D by sphingosine involves both protein kinase C-dependent and -independent mechanisms in NIH 3T3 fibroblasts." Biochemical Journal 288, no. 3 (December 15, 1992): 853–58. http://dx.doi.org/10.1042/bj2880853.
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Previously, the protein kinase C (PKC) inhibitor sphingosine was found to stimulate phospholipase D (PLD)-mediated hydrolysis of both phosphatidylethanolamine (PtdEtn) and phosphatidylcholine (PtdCho) in NIH 3T3 fibroblasts [Kiss & Anderson (1990) J. Biol. Chem. 265, 7345-7350]. Here we examined the possible relationship between the opposite effects of sphingosine on PKC-mediated protein phosphorylation and PLD activation. After treatments for 3-5 min, sphingosine (25 microM) and the PKC activators phorbol 12-myristate 13-acetate (PMA) (100 nM), bryostatin (100 nM) or platelet-derived growth factor (50 ng/ml) synergistically stimulated the hydrolysis of both PtdEtn and PtdCho in NIH 3T3 fibroblasts prelabelled with [14C]ethanolamine or [14C]choline. Inhibition of PMA-induced phospholipid hydrolysis could also be elicited by sphingosine, but this process required prolonged (60 min) treatments of fibroblasts with 40-60 microM-sphingosine. Similarly to sphingosine, the protein phosphatase inhibitor okadaic acid also had either potentiating or inhibitory effects on PMA-stimulated PLD activity, depending on the length of incubation time and the concentration of PMA. Consistent with the presence of an inhibitory component in the overall action of PKC, the PKC inhibitor staurosporine and down-regulation of PKC activity by prolonged (24 h) treatment with PMA similarly enhanced PLD activity. Data suggest that (a) sphingosine may enhance PMA-mediated phospholipid hydrolysis by neutralizing the action of an inhibitory PKC isoform, and that (b) the stimulatory PKC isoform is less sensitive to the inhibitory action of sphingosine.
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Shey, Susan, Sarah Kim, Julie Kim, and Elizabeth J. Murphy. "Phosphoinositide 3-Kinase Inhibitor-Induced Hyperglycemia." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A394—A395. http://dx.doi.org/10.1210/jendso/bvab048.803.
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Abstract Background: Phosphoinositide 3-kinase inhibitors (PI3Ki) are a new class of medications used to treat HR positive, HER2 negative, PIK3CA mutated advanced or metastatic breast cancer. Inhibition of PI3K, a key enzyme in the insulin signaling pathway, leads to disruption of glucose metabolism and frequently hyperglycemia. Here we present a case of difficult to treat PI3Ki-induced hyperglycemia from alpelisib. Case: 78 yo woman with metastatic breast cancer and NASH cirrhosis was referred for new hyperglycemia after starting alpelisib. Baseline HbA1c was 6%. She was initially started on metformin and glipizide without any blood glucose (BG) improvement. After 6 days, alpelisib was held with BG recovery. Alpelisib was restarted 1 month later, again resulting in hyperglycemia. Dapagliflozin treatment quickly improved BG to <200 mg/dL, but she developed candida intertrigo so it was discontinued and insulin was started. She also began a ketogenic diet. After 2 weeks of insulin titration, she had stable BG <200 on 47u of insulin a day. Within days, she was admitted with encephalopathy and a UTI which improved with antibiotics and lactulose. Alpelisib, initially held, was restarted on day 2 resulting in worsening hyperglycemia. Inpatient BG ranges on alpelisib were: fasting 191–358, pre-lunch 260–383, pre-dinner 308–404, and bedtime 330–355, despite a rapid increase of basal-bolus insulin and initiation of metformin, pioglitazone, and a ketogenic diet. Total daily insulin needs went from 18u, to 124u by day 5 of alpelisib. Imaging revealed new bone and hepatic metastases. With difficult to control hyperglycemia and cancer progression, alpelisib was discontinued with rapid improvement of hyperglycemia. Discussion: Hyperglycemia is a common adverse and on target effect of PI3Ki use. PI3K inhibition leads to acute hyperglycemia within hours. The pancreas responds by increasing insulin release. Transient hyperglycemia can occur in all patients, but may become persistent with underlying insulin resistance, as seen in our patient. T2DM (with HbA1c >6.5%) and all T1DM patients were excluded in alpelisib trials yet diabetes is not a formal contraindication. Providers should be vigilant for this complication in patients with diabetes and prediabetes. It has been suggested that exogenous insulin and medications that increase endogenous insulin secretion may be counterproductive because they overcome PI3Ki-induced insulin signaling disruption and compromise anti-tumor effectiveness of PI3Ki. Thus, the preferred and most effective treatment may be an SGLT2i as was the case in our patient. Insulin sensitizers and a ketogenic diet can potentially also be effective. Increasing insulin may have limited efficacy as seen with our patient. Future studies are needed to determine the best way to manage PI3Ki-induced hyperglycemia and the effect of potential treatments on anti-tumor efficacy.
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Artamonova, E. V., and E. I. Kovalenko. "Hormone therapy for premenopausal women with metastatic breast cancer: combinations with cyclin-dependent kinase inhibitors." Tumors of female reproductive system 15, no. 2 (September 6, 2019): 30–41. http://dx.doi.org/10.17650/1994-4098-2019-15-2-30-41.
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This article discusses the problems associated with the search of the most effective treatment strategies for HER2-negative metastatic breast cancer in premenopausal women. Until recently, ovarian suppression and hormone therapy had been the main treatments used in this group of patients. The development of palbociclib, called a “breakthrough therapy”, as well as promising results of trials evaluating the efficacy of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors added to hormone therapy in postmenopausal women suggested a need for the assessment of this treatment regimen in combination with ovarian suppression in younger patients.According to the results of randomized trials and subgroup analysis, the addition of a CDK4/6 inhibitor to ovarian suppression and hormonal therapy significantly increases survival. The safety profile is similar to that of older patients. Randomized trials comparing the efficacy of palbociclib + ovarian suppression + aromatase inhibitor vs. chemotherapy in premenopausal women demonstrated significant benefits of a new treatment strategy: a CDK4/6 inhibitor as a part of combination therapy reduced the risk of progression by 36 % compared to capecitabine.
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Chen, Lisa S., William G. Wierda, Sanjeev Redkar, David J. Bearss, and Varsha Gandhi. "Pim Kinase Inhibitor, SGI-1776, Induces Apoptosis in CLL Lymphocytes." Blood 112, no. 11 (November 16, 2008): 4199. http://dx.doi.org/10.1182/blood.v112.11.4199.4199.
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Abstract We report investigational studies of a Pim-1 kinase inhibitor, SGI-1776, as a therapeutic agent for the treatment of chronic lymphocytic leukemia (CLL). Pim family proteins are serine/threonine kinase inhibitors of apoptosis, and elevated expression of Pim kinases have been detected in hematological malignancies and in certain solid tumors. Three Pim kinases have been identified to date, Pim-1, -2 and -3. Pim-1 has been shown to synergize with c-Myc in tumorigenesis, and increased expression of the human Pim-2 gene is observed in CLL and non-Hodgkin lymphomas. Specifically, Pim-1 and Pim-2 have been shown to be required for efficient pre–B-cell transformation by v-Abl oncogene. Small molecule SGI-1776 was evaluated using Ambit Biosciences’ KINOMEscan and was found to have IC50s in the nanomolar range for Pim-1, Pim-2, and Pim-3 using the Millipore IC50 Profiler. SGI-1776 was screened against a panel of kinases utilizing radiolabeled biochemical assays, and was found to be highly selective for Pim kinases without any effects on CDKs, Chk1, IKK, JNK, Abl, Raf, MAP kinases and protein kinase A and B. Specifically, the IC50 were measured as follows: Pim-1 (7 nM), Pim-2 (363 nM) and Pim-3 (69 nM.) The other two enzymes affected at nM concentration of SGI-1776 were Flt-2 and haspin. Using primary samples obtained from patients with CLL, we evaluated the potential for SGI-1776 to induce cell death. In vitro incubation of primary CLL cells (n=7), with 1, 3, and 10 μM SGI-1776 for 24 h resulted in an average increase in apoptosis of 10%, 22% and 38% respectively, compared with untreated cells. SGI-1776-induced apoptosis was observed in heterogeneous patient populations, and there was disparity in the expression levels of traditional CLL prognostic markers including ZAP-70, b2-microglobulin, IgVH mutation status, Rai stage and number of prior treatments. To elucidate its mechanism of action, we evaluated the effect of SGI-1776 on Pim kinase function. Phosphorylation of traditional Pim-1 kinase targets, phospho-Bad (Ser112) and histone H3 (Ser10) were not affected by SGI-1776 treatment in CLL, unlike in replicating cell types, suggesting an alternative mechanism in CLL. We then evaluated the potential inhibition of c-Myc driven transcription by measuring total RNA synthesis. Following treatment with 3 or 10 μM SGI-1776, there was a decrease in total RNA synthesis to approximately 50% of control, measured using a radioactive uridine incorporation assay (n = 3). There was also a reduction in Mcl-1 and c-Myc protein level, both of which have short transcript half-lives. The reduction in Mcl-1 protein was not due to apoptosis or cleavage by caspases, since Mcl-1 reduction occurred in the presence of caspase inhibitor ZVAD, nor was there an increase in cleaved Mcl-1. In contrast, there was no change in anti-apoptotic proteins Bcl-2, XIAP, survivin, stabilization of p53 or p21. Taken together, SGI-1776 consistently induced apoptosis in CLL cells. Although its mechanism of action is not fully elucidated, inhibition of RNA synthesis and reduction of Mcl-1 and c-Myc protein levels are associated with SGI-1776-induced apoptosis.
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Jacob, Allen, Jaret Shook, and Thomas E. Hutson. "Tivozanib, a highly potent and selective inhibitor of VEGF receptor tyrosine kinases, for the treatment of metastatic renal cell carcinoma." Future Oncology 16, no. 28 (October 2020): 2147–64. http://dx.doi.org/10.2217/fon-2020-0443.
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The VHL mutation– HIF upregulation– VEGF transcription sequence is the principal pathway in the development of renal cell carcinoma. Tyrosine kinase inhibitors target the VEGF receptors to inhibit further growth of renal cell carcinoma tumors. Tivozanib, originally named AV-951 and KRN-951, is a novel, orally bioavailable VEGF tyrosine kinase inhibitor that is selective for VEGF receptors 1, 2 and 3. Further, only picomolar concentrations of tivozanib are required to target these VEGF receptors and prevent phosphorylation; this potency prevents the debilitating side effects that occur with treatments whose mechanisms of action involve broad-spectrum tyrosine kinase inhibition. This review summarizes the growing body of evidence supporting tivozanib's efficacy and safety in the treatment of advanced renal cell carcinoma.
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Ciereszko, R., M. Opalka, B. Kaminska, T. Górska, and L. Dusza. "Prolactin signalling in porcine theca cells: the involvement of protein kinases and phosphatases." Reproduction, Fertility and Development 15, no. 1 (2003): 27. http://dx.doi.org/10.1071/rd02049.
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The hypothesis that protein kinase C (PKC) and tyrosine kinases, as well as serine–threonine and tyrosine phosphatases, are involved in prolactin (PRL) signalling in theca cells harvested from porcine follicles was tested. Theca cells were incubated with PRL for 24 h to stimulate progesterone (P4) production. In addition, treatments included inhibitors of PKC and tyrosine kinases, as well as serine–threonine phosphatase inhibitor and tyrosine phosphatase inhibitor. Prolactin significantly stimulated P4 production by theca cells and all inhibitors suppressed the PRL-stimulated P4 production. After incubation with PRL for 2, 5, 10 or 20 min, theca cells were homogenized and cytosolic and membrane fractions were obtained. This was followed by determination of PKC activity in partially purified subcellular fractions by measuring the transfer of 32P from [γ−32P] adenosine triphosphatase (ATP) to histone III-S. In unstimulated porcine theca cells the major proportion of PKC activity was present in the cytosol. Incubation of cells with PRL resulted in a rapid, time-dependent increase in the amount of PKC activity in the membrane fraction. Protein kinase C activity in the membrane fraction was maximal after 10 min of cells’ exposure to PRL. Protein kinase C activation was assessed also by measuring the specific association of 3H-phorbol dibutyrate (3H-PDBu) with theca cells after treatment with PRL. Prolactin significantly increased 3H-PDBu-specific binding in theca cells. In contrast to PKC, total inositol phosphate accumulation was not affected by PRL in the current study. In summary, PRL stimulated P4 production by porcine theca cells derived from large follicles. The results of the study were consistent with the hypothesis that PKC is one of the intracellular mediators of PRL action in porcine theca cells. Protein kinase C activation does not appear to occur through the action of phosphatidylinositol-dependent phospholipase C. Moreover, the involvement of tyrosine kinases, as well as tyrosine and serine–threonine phosphatases, in PRL signalling in the examined cells is suggested.
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Molina-Arcas, Miriam, Christopher Moore, Sareena Rana, Febe van Maldegem, Edurne Mugarza, Pablo Romero-Clavijo, Eleanor Herbert, et al. "Development of combination therapies to maximize the impact of KRAS-G12C inhibitors in lung cancer." Science Translational Medicine 11, no. 510 (September 18, 2019): eaaw7999. http://dx.doi.org/10.1126/scitranslmed.aaw7999.
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KRAS represents an excellent therapeutic target in lung cancer, the most commonly mutated form of which can now be blocked using KRAS-G12C mutant-specific inhibitory trial drugs. Lung adenocarcinoma cells harboring KRAS mutations have been shown previously to be selectively sensitive to inhibition of mitogen-activated protein kinase kinase (MEK) and insulin-like growth factor 1 receptor (IGF1R) signaling. Here, we show that this effect is markedly enhanced by simultaneous inhibition of mammalian target of rapamycin (mTOR) while maintaining selectivity for the KRAS-mutant genotype. Combined mTOR, IGF1R, and MEK inhibition inhibits the principal signaling pathways required for the survival of KRAS-mutant cells and produces marked tumor regression in three different KRAS-driven lung cancer mouse models. Replacing the MEK inhibitor with the mutant-specific KRAS-G12C inhibitor ARS-1620 in these combinations is associated with greater efficacy, specificity, and tolerability. Adding mTOR and IGF1R inhibitors to ARS-1620 greatly improves its effectiveness on KRAS-G12C mutant lung cancer cells in vitro and in mouse models. This provides a rationale for the design of combination treatments to enhance the impact of the KRAS-G12C inhibitors, which are now entering clinical trials.
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Wen, Ji, Huifang Hu, Menglin Chen, Hang Yang, Yi Zhao, and Yi Liu. "Role of Janus Kinase (JAK) Inhibitor in Autoimmune Ocular Inflammation: A Systematic Review." Journal of Immunology Research 2021 (December 20, 2021): 1–9. http://dx.doi.org/10.1155/2021/2324400.
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Purpose. To evaluate the effectiveness of Janus kinase (JAK) inhibitors for the treatment of patients with autoimmune disease and associated inflammatory ocular diseases. Methods. We identified relevant literature by screening the MEDLINE, PubMed, and Cochrane databases for randomized controlled trials, cohort studies, case controls, and case reports. Results. Seven studies, including 11 patients, were included in the final systematic analysis. Of the 11 patients, there were 5 cases of juvenile idiopathic arthritis- (JIA-) associated uveitis, 1 case of rheumatoid arthritis- (RA-) associated keratitis, 1 case of RA-associated scleritis, 1 case of psoriasis-associated conjunctivitis, 2 cases of noninfectious scleritis, and 1 case of uveitis with suspected autoimmune disease. None of these 11 patients responded adequately to conventional treatments, including biological agents; these were all refractory cases and switched to JAK inhibitor therapy. Irrespective of whether they were suffering from uveitis, scleritis, or other types of ocular inflammation, all 11 patients showed an improvement to JAK inhibitors without significant side effects. Different types of JAK inhibitors might be associated with different responses when used to treat ocular inflammation. Conclusions. JAK inhibitors may represent an alternative treatment option for patients with autoimmune ocular inflammation.
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DeSilva, Dimuthu R., Elizabeth A. Jones, Margaret F. Favata, Bruce D. Jaffee, Ronald L. Magolda, James M. Trzaskos, and Peggy A. Scherle. "Inhibition of Mitogen-Activated Protein Kinase Kinase Blocks T Cell Proliferation But Does Not Induce or Prevent Anergy." Journal of Immunology 160, no. 9 (May 1, 1998): 4175–81. http://dx.doi.org/10.4049/jimmunol.160.9.4175.
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Abstract Three mitogen-activated protein kinase pathways are up-regulated during the activation of T lymphocytes, the extracellular signal-regulated kinase (ERK), Jun NH2-terminal kinase, and p38 mitogen-activated protein kinase pathways. To examine the effects of blocking the ERK pathway on T cell activation, we used the inhibitor U0126, which has been shown to specifically block mitogen-activated protein kinase/ERK kinase (MEK), the kinase upstream of ERK. This compound inhibited T cell proliferation in response to antigenic stimulation or cross-linked anti-CD3 plus anti-CD28 Abs, but had no effect on IL-2-induced proliferation. The block in T cell proliferation was mediated by down-regulating IL-2 mRNA levels. Blocking Ag-induced proliferation by inhibiting MEK did not induce anergy, unlike treatments that block entry into the cell cycle following antigenic stimulation. Surprisingly, induction of anergy in T cells exposed to TCR cross-linking in the absence of costimulation was also not affected by blocking MEK, unlike cyclosporin A treatment that blocks anergy induction. These results suggest that inhibition of MEK prevents T cell proliferation in the short term, but does not cause any long-term effects on either T cell activation or induction of anergy. These findings may help determine the viability of using mitogen-activated protein kinase inhibitors as immune suppressants.
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YILDIZ, Çağlar, Zeki ÖZSOY, Turgut KACAN, and Hatice ÖZER. "The Effects of Lapatinib and Trastuzumab in a Rat Model of Endometriosis." Cumhuriyet Science Journal 43, no. 4 (December 27, 2022): 556–63. http://dx.doi.org/10.17776/csj.1168698.
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Trastuzumab and lapatinib are drugs belonging to tyrosine kinase inhibitors family that are used in cancer treatment to prevent cell proliferation. Trastuzumab is an inhibitor of human epidermal growth factor receptor–2 (HER2) tyrosine kinase, and lapatinib is an inhibitor of epidermal growth factor receptor (EGFR). Tyrosine kinase inhibitors have also been investigated for treatment of endometriosis. In the present study, we aimed to investigate the effects of lapatinib and trastuzumab on rat endometriosis model. Endometriosis was surgically induced by the autologous transplantation of endometrial tissue and formation of endometriosis was confirmed via secondary laparotomy in 32 rats. Initially, 4 mg/kg dose of trastuzumab was applied intraperitoneally, and two additional doses of 2 mg/kg were applied 7 days and 14 days after the initial dose. Lapatinib was administered as 100 mg/kg daily doses for 14 days. Rats were randomly divided into four groups and were subjected to lapatinib, trastuzumab, anastrozole (0.004 mg/day, p.o.) and normal saline (0.1 ml, i.p.) treatments for 14 days. Then, endometriosis foci were excised, and endometriosis scores were calculated in a semi-quantitative manner. Immunohistochemical (IHC) examinations were also performed using VEGF, CD117 and Bax antibodies. Both anastrozole and tyrosine kinase inhibitors lowered endometriosis scores. Significant decreases in ovarian follicle numbers were observed in lapatinib and anastrozole groups but not trastuzumab group. Lapatinib and trastuzumab decreased endometriotic foci through suppressing cell proliferation and promoting programmed cell death.
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Master, Samip R., and Richard Preston Mansour. "Cardiovascular Toxicities of Tyrosine Kinase Inhibitor in CML." Blood 136, Supplement 1 (November 5, 2020): 6. http://dx.doi.org/10.1182/blood-2020-143216.
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Background: Cardiovascular (CV) toxicity is a known toxicity of tyrosine kinase inhibitors (TKI) used for chronic myeloid leukemia (CML). Imatinib, dasatinib, nilotinib and bosutinib are all approved for first line treatment for CML. We did a retrospective analysis on adverse effects (AE) of TKIs that has been made available to public by the FDA. Methods: The FDA has made the data on AEs of various treatments available to general public through the FDA Adverse Events Reports System (FAERS) public dashboard. We investigated the CV AEs of various TKIs for the years 2017-2019. Results: The percentage of CV AE compared to total AEs reported for Imatinib, Dasatinib, Bosutinib , Nilotinib and Ponatinib were 7.2%, 10.5%, 15.8%, 23.4% and 23.5% respectively. The percentage of CV AE leading to death for Imatinib, Dasatinib, Bosutinib , Nilotinib and Ponatinib were 8.3%, 9.1%, 9.1%, 13.7 % and 18.6% respectively. Conclusions: Out of the reported cases of AEs to TKIs approved for front line CML, nilotinib appears to have more CV AE compared to imatinib, dasatinib and bolutinib. Imatinib appears to have least CV AE out of the total AEs reported Disclosures No relevant conflicts of interest to declare.
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Bayley, A., and N. Gullick. "SAT0420 EFFICACY OF NON-TUMOUR NECROSIS FACTOR BIOLOGICS AND TARGETED SYSTEMIC DISEASE MODIFYING ANTI-RHEUMATIC DRUGS IN THE TREATMENT OF PSORIATIC ARTHRITIS: A SYSTEMATIC REVIEW AND META-ANALYSIS." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1163–64. http://dx.doi.org/10.1136/annrheumdis-2020-eular.4742.
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Background:Psoriatic arthritis (PsA) is a systemic, inflammatory condition presenting in approximately 30% of patients with psoriasis and associated with functional impairment and a reduced health-related quality of life. Current treatment guidelines recommend non-steroidal anti-inflammatory drugs, conventional Disease Modifying Anti-Rheumatic Drugs (cDMARDs) and Tumour Necrosis Factor α inhibitors (TNFi). Recent research has focused on alternative biologic medications which target interleukin (IL) 6, 12/23, 17A, 23 and T Cell co-stimulation, as well as targeted synthetic DMARDs (tsDMARDs) including Janus Kinase inhibitors (JAKi) and Phosphodiesterase 4 inhibitors (PDE4i). Evidence of the safety and efficacy, measured using the American College of Rheumatology-20 (ACR20), has been demonstrated leading to the inclusion of several biologics and tsDMARDs in guidelines. However, it can be argued that ACR50, indicating a 50% improvement in disease, is a more clinically relevant outcome measure.Objectives:To conduct a systematic review and meta-analysis of the efficacy (ACR50 response) of non-TNFi biologics and tsDMARDs in the treatment of PsA.Methods:A systematic literature search of Embase, MedLine and Web of Science was undertaken to identify randomised controlled trials (RCTs) investigating efficacy and safety of non-TNFi biologics and tsDMARDs published in English from the inception of the databases to September 2019. The Cochrane Risk of Bias tool was used to assess methodological rigour of included trials. A meta-analysis was performed using a random effects model to estimate odds ratios of ACR 50 response vs placebo. A subgroup analysis was performed using patients with previous TNFi exposure.Results:21 RCTs were eligible with 6389 participants. Evaluation periods ranged from 12 to 24 weeks. JAKi, PDE4i, IL6i, IL12/23i, IL17Ai and IL23i treatments were more efficacious than placebo for ACR50 response (p<0.001) (Figure 1). Only tofacitinib (JAKi), secukinumab (IL17Ai) and ixekizumab (IL17Ai) were able to demonstrate efficacy at the ACR50 level in participants with prior TNFi exposure (p<0.0001) (Figure 2). All treatments demonstrated an adequate safety profile.Figure 1.Forest plot of achieving American College of Rheumatology-50 with treatment versus placebo M-H, Mantel-Haenzel; CI, confidence interval; JAKi, Janus Kinase inhibitor; PLA, placebo; df, degrees of freedom; PDE4i, Phosphodiesterase 4 inhibitor; IL6Ai, Interleukin 6 inhibitor; IL12/23i, Interleukin 12/23 inhibitor; IL17Ai, Interleukin 17A inhibitor; TNFi, Tumour necrosis factor inhibitor; IL23i, Interleukin 23 inhibitorFigure 2.Forest plot of achieving American College of Rheumatology-50 with treatment versus placebo in tumour necrosis factor inhibitor-exposed subgroup M-H, Mantel-Haenzel; CI, confidence interval; JAKi, Janus Kinase inhibitor; PLA, placebo; df, degrees of freedom; PDE4i, Phosphodiesterase 4 inhibitor; IL6Ai, Interleukin 6 inhibitor; IL12/23i, Interleukin 12/23 inhibitor; IL17Ai, Interleukin 17A inhibitor; IL23i, Interleukin 23 inhibitorConclusion:Non TNFi biologics and tsDMARDs are able to demonstrate 50% improvement with adequate safety profiles. These therapies are often used in patients who are inadequate responders to TNFi but there is less robust data in this specific patient group. Studies with clinically relevant primary endpoints should be considered in this patient population.Disclosure of Interests:None declared
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Soleimani, Maryam, Lucia Nappi, and Christian Kollmannsberger. "Avelumab and axitinib combination therapy for the treatment of advanced renal cell carcinoma." Future Oncology 16, no. 36 (December 2020): 3021–34. http://dx.doi.org/10.2217/fon-2020-0586.
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Owing to an improved understanding of the immunobiological profile of renal cell carcinoma (RCC), the past few years have ushered in significant changes in systemic therapies for advanced stage RCC. First-line treatment with single-agent tyrosine kinase inhibitors (TKI) has been virtually replaced for most patients by immunotherapy combinations. The first of such treatments was the dual immune checkpoint inhibitor combination of ipilimumab and nivolumab. More recently, the combination of an immune checkpoint inhibitor and a TKI has also moved into the first-line setting. This review summarizes the pharmacologic properties, evidence for use and safety of avelumab, a PD-L1 inhibitor and axitinib a small-molecule TKI, each as monotherapy, and in combination for the management of metastatic RCC.
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Okabe, Seiichi, Tetsuzo Tauchi, Seiichiro Katagiri, Yuko Tanaka, and Kazuma Ohyashiki. "Activity of the Aurora Kinase Inhibitor, MLN8237 (alisertib) Alone or in Combination with Ponatinib Against Imatinib-Resistant BCR-ABL-Positive Cells." Blood 120, no. 21 (November 16, 2012): 1333. http://dx.doi.org/10.1182/blood.v120.21.1333.1333.
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Abstract Abstract 1333 Chronic myeloid leukemia (CML) is characterized by cytogenetic aberration (Philadelphia chromosome: Ph) and chimeric tyrosine kinase BCR-ABL. ABL tyrosine kinase inhibitor, imatinib has demonstrated the potency against CML patients. However, resistance to imatinib can develop in CML patients due to BCR-ABL point mutations. One of T315I mutation is resistant to currently available ABL tyrosine kinase inhibitors. Therefore, new approach against T315I mutant may improve the outcome of Ph-positive leukemia patients. Aurora kinases are serine/threonine kinases and upregulated in many malignancies including leukemia, and play an important role in cell cycle control and tumor proliferations. Because Aurora kinases are overexpressed in leukemia cells, Aurora kinases may present attractive targets for leukemia treatment. One of Aurora kinase inhibitor, MLN8237 (alisertib) is an oral and selective Aurora kinase A inhibitor and is currently being investigated in a pivotal phase 3 clinical trial against hematological malignancies. We suggested that alisertib mediated inhibition Aurora kinase activity and in combination with ponatinib, also known as AP24534 may abrogate the proliferation and survival of Ph-positive cells including T315I mutation. In this study, we investigated the combination therapy with a ponatinib and an alisertib by using the BCR-ABL positive cell line, K562, murine Ba/F3 cell line which was transfected with T315I mutant, ponatinib resistant Ba/F3 cells and T315I primary sample. Protein expression of Aurora A and B were increased in Ph-positive leukemia cells. 72 hours treatment of alisertib exhibits cell growth inhibition and induced apoptosis against K562 cells in a dose dependent manner. Alisertib also induced cell cycle arrest. The treatment of ponatinib exhibits cell growth inhibition partially against K562 cells in the presence of feeder cell (HS-5) conditioned media. We found that the treatment of alisertib abrogated the protective effects of HS-5 conditioned media in K562 cells. We investigated the alisertib activity against T315I positive cells. Alisertib potently induced cell growth inhibition of Ba/F3 cells ectopically expressing T315I mutation and induced cell cycle arrest. We investigated the efficacy between ponatinib and alisertib by using these cell lines. Combined treatment of Ba/F3 T315I cells with ponatinib and alisertib caused significantly more cytotoxicity than each drug alone. Ponatinib and alisertib were also effective against T315I primary samples. We examined the intracellular signaling of alisertib. Phosphorylation of Aurora A was inhibited in a time dependent manner. We also found the phosphorylation of histone H3 was also reduced in a dose dependent manner suggested that high concentration of alisertib also inhibits Aurora B activity. We next investigated by using ponatinib resistant Ba/F3 cells. In the ponatinib resistant cell lines, IC50 of ponatinib was up to 200 nM. BCR-ABL triple point mutations (T315I, E255K and Y253H) were detected by direct sequence analysis. The treatment of alisertib exhibits cell growth inhibition against Ba/F3 ponatinib resistant cells in the dose dependent manner. Alisertib induced cell cycle arrest in ponatinib resistant cells. Combined treatment of Ba/F3 ponatinib resistant cells with ponatinib and alisertib caused significantly more cytotoxicity. To assess the activity of alisertib and ponatinib, we performed to test on CML tumor formation in mice. We injected nude mice subcutaneously with 1×107 Ba/F3 T315I cells. A dose of 30 mg/kg/day p.o of ponatinib and 30 mg/kg/day p.o of alisertib inhibited tumor growth and reduced tumor volume compared with control mice. The treatments were well tolerated with no animal health concerns observed indicating the feasibility of alisertib combination strategies in the clinic. Data from this study suggested that administration of the ponatinib and Aurora inhibitor, alisertib may be a powerful strategy against BCR-ABL mutant cells including T315I. Disclosures: No relevant conflicts of interest to declare.
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Hu, Xiangyang, Steven J. Neill, Weiming Cai, and Zhangcheng Tang. "Nitric oxide mediates elicitor-induced saponin synthesis in cell cultures of Panax ginseng." Functional Plant Biology 30, no. 8 (2003): 901. http://dx.doi.org/10.1071/fp03061.
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The elicitor oligogalacturonic acid (OGA) stimulated nitric oxide (NO) accumulation in the growth medium of ginseng suspension cultures and induced increased nitric oxide synthase (NOS) activity in ginseng cells. OGA also stimulated accumulation of saponin, transcription of genes encoding squalene synthase (sqs) and squalene epoxidase (sqe), two early enzymes of saponin synthesis, and the accumulation of β-amyrin synthase protein (β-AS). Saponin accumulation, sqs and sqe gene expression, and increases in β-AS content were also induced by exposure to NO via the NO donor sodium nitroprusside (SNP). Inhibitors of mammalian nitric oxide synthase reduced both OGA-induced NO accumulation and NOS activity, suggesting that OGA-induced NO production occurs via a NOS-like enzyme. OGA-induced accumulation of β-AS and saponin, and transcription of sqs and sqe, were suppressed by treatments that removed NO or inhibited its production, indicating a role for NO in mediating OGA effects on these defence responses. NO accumulation and increased NOS activity were inhibited by calcium channel inhibitors and a protein kinase inhibitor, but not by a protein phosphatase inhibitor, indicating the requirement for calcium and protein phosphorylation during OGA-induced NO production. Saponin production and transcription, and accumulation of saponin biosynthetic genes and enzymes were also suppressed by these treatments, as well as by the protein phosphatase inhibitor okadaic acid.
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Karamsetty, M. R., J. R. Klinger, and N. S. Hill. "Evidence for the role of p38 MAP kinase in hypoxia-induced pulmonary vasoconstriction." American Journal of Physiology-Lung Cellular and Molecular Physiology 283, no. 4 (October 1, 2002): L859—L866. http://dx.doi.org/10.1152/ajplung.00475.2001.
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Mitogen-activated protein (MAP) kinases regulate smooth muscle cell contraction. Hypoxia contracts pulmonary arteries by mechanisms that are incompletely understood. We hypothesized that hypoxic contraction of pulmonary arteries involves activation of the MAP kinases. To test this hypothesis, we studied the effects of SB-202190, a p38 MAP kinase inhibitor, PD-98059 and UO-126, two structurally different MEKK inhibitors, and anisomycin, a stimulator of p38 MAP kinase on acute hypoxia-induced contraction in rat conduit pulmonary artery rings precontracted with phenylephrine or KCl. Hypoxia induced a transient contraction, followed by a relaxation, and then a slowly developing sustained contraction. Hypoxia also significantly increased phosphorylation of p38 MAP kinase. SB-202190 did not affect the transient phase but abrogated the sustained phase of hypoxic contraction, whereas anisomycin enhanced both phases of contraction. SB-202190 also attenuated and anisomycin enhanced the phenylephrine-induced contraction. In contrast, PD-98059 and UO-126 had minimal effects on either hypoxic or phenylephrine-induced contraction. None of the treatments modified KCl-induced contraction. We conclude that p38, but not the ERK1/ERK2 MAP kinase pathway, mediates the sustained phase of hypoxic contraction in isolated rat pulmonary arteries.
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Covey, Todd M., Michael Gulrajani, Heiko Becker, Jason C. Chandler, Sebastian Schwind, Guido Marcucci, and Alessandra Cesano. "Single Cell Network Profiling as a Platform to Reveal Leukemia-Specific Signaling Signatures and Sensitivity to Kinase Inhibitor Therapies." Blood 116, no. 21 (November 19, 2010): 2753. http://dx.doi.org/10.1182/blood.v116.21.2753.2753.
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Abstract Abstract 2753 Aberration in kinase activity by either the gain-of-function mutations or overexpression of the encoding genes plays a pivotal role in myeloid leukemogenesis. An increasing number of kinase inhibitors are being developed as “targeted therapies” for the treatment of acute myeloid leukemia (AML) and other myeloproliferative disorders. However, given the biologic and clinical heterogeneity inherent to these diseases, an unmet medical need exists for tools to guide the choice of inhibitor(s) most relevant for individual patients. With the aim of developing a platform for the biological characterization of patient-specific tumors, which could assist patient stratification strategies for clinical trials, we combined signaling pathway analysis and drug response profiling in AML samples using Single Cell Network Profiling (SCNP) assays. This technology allows for the simultaneous measurement of the activation state of multiple signaling proteins at the single cell level. Cryopreserved mononuclear cells from blood leukapheresis of patients with AML (N=6) were analyzed in two experimental arms. #1 Signaling Arm: A panel of kinase inhibitors targeting FLT3, cKit, PI3 kinase, mTor, MEK, and JAK proteins was added at varying concentrations to the AML cells followed by stimulation with G-CSF, IL-27, cKit ligand (SCF), FLT3 ligand (FLT3L), or a vehicle control. Using multiparameter flow cytometry, the phosphoylation status of AKT, ERK, S6 Ribosome, STAT1, STAT3, and STAT5 were measured in multiple leukemia cell subsets defined by expression of CD34, cKit, CD3, and light scatter properties. Per sample, there were a total of 68 treatments measuring 3 phospho-proteins in 3 cell subsets. #2 Apoptosis/Cytostasis Arm: The leukemic cells were driven into cell cycle by exposure to IL-3, SCF, and FLT3L, followed by a 48-hr incubation with a combination of 1 to 5 kinase inhibitors targeting the same pathways referred to previously. The kinase inhibitor impact was measured on distal functional readouts, including apoptosis (cleaved PARP) and cell cycle (CyclinB1-S/G2 phase; p-Histone H3-M phase). These results were compared with results using bone marrow samples from healthy donors (N=6). Results: Each patient's sample generated a unique signaling profile. A broad range of protein-specific phosphorylation status of AKT, ERK, S6 Ribosome, STAT1, STAT3, and STAT5 was observed in response to growth factor stimulation. Response was measured by setting a region gate that captures the overall percentage of cells with fluorescence above the unstimulated level. The percentage of SCF, G-CSF and FLT3L responsive cells ranged between 6%-49%, 3%-56%, and 3%-22%, respectively. Overall, patient samples could be grouped based on their signaling profile, proliferative potential, and sensitivity to kinase inhibitor treatment. Specifically, the 2 samples with the greatest SCF and G-CSF signaling response also showed the most robust in vitro proliferation and were most sensitive to the JAK inhibitor, CP-690,550 (1μM) (as measured by cytostasis readouts). Whereas, 2 other samples that displayed only modest SCF and G-CSF signaling, but robust FLT3L signaling expanded slowly in culture and were particularly sensitive to the cytostatic effects of the PI3K inhibitor, GDC-0941, (1uM) or the Flt3 inhibitor, tandutinib, (1uM). Finally, the last 2 AML samples had weak growth factor signaling and did not proliferate in culture and therefore could not be tested for kinase inhibitor-induced cytostasis. While the successfully tested patient samples showed variable sensitivity (as measured by cytostasis and apoptosis) to different drug combinations, the samples from healthy donors showed considerable similarity in response across all inhibitor combinations. Conclusions: This study provides preliminary proof-of-concept on the utility of SCNP to dissect the pathophysiologic heterogeneity of hematologic tumors and assess their differential response to single and combination therapies. Ultimately, this functional pathway profiling and drug sensitivity assay may be useful to stratify patients to different kinase combination treatments tested in clinical trials. Disclosures: Covey: Nodality Inc.: Employment, Equity Ownership. Gulrajani:Nodality Inc.: Employment, Equity Ownership. Cesano:Nodality Inc.: Employment, Equity Ownership.
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Dai, Jun, LiXi Yang, and Glynn Addison. "Current Status in the Discovery of Covalent Janus Kinase 3 (JAK3) Inhibitors." Mini-Reviews in Medicinal Chemistry 19, no. 18 (November 29, 2019): 1531–43. http://dx.doi.org/10.2174/1389557519666190617152011.
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The search for inhibitors of the Janus kinase family (JAK1, JAK2, JAK3 and TYK2) has been ongoing for several decades and has resulted in a number of JAK inhibitors being approved for use in patients, such as tofacitinib for the treatment of autoimmune diseases such as Rheumatoid Arthritis (RA). Although initially thought to be a JAK3 selective inhibitor, tofacitinib was subsequently found to possess significant activity to inhibit JAK1 and JAK2 which has contributed to some adverse side effects. A selective JAK3 inhibitor should only have an effect within the immune system since JAK3 is solely expressed in lymphoid tissue; this makes JAK3 a target of interest in the search for treatments of autoimmune diseases. A method to obtain selectivity for JAK3 over the other JAK family members, which has attracted more scientific attention recently, is the targeting of the active site cysteine residue, unique in JAK3 within the JAK family, with compounds containing electrophilic warheads which can form a covalent bond with the nucleophilic thiol of the cysteine residue. This review encompasses the historical search for a covalent JAK3 inhibitor and the most recently published research which hasn’t been reviewed to date. The most important compounds from the publications reviewed the activity and selectivity of these compounds together with some of the more important biological results are condensed in to an easily digested form that should prove useful for those interested in the field.
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Conley, B. A., C. M. Leece, S. Chandana, and S. Dowlashati. "Role of mixed lineage kinase 3 in response of head and neck squamous cancer cell lines to epidermal growth factor receptor (EGFR) inhibition." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 6076. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.6076.
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6076 Background: More efficacious treatments of head and neck squamous cancers (HNSCC) are urgently needed. HNSCC overexpress EGFR, yet the efficacy of EGFR inhibitors is marginal, with minimal effect on patient survival. Mixed lineage kinases (MLKs) are members of a large family of mitogen-activated protein kinase (MAPK) kinase kinases (MAPKKKs) that activate MAPK pathways, involving JNK, ERK 1/2 and p38 cell signaling pathways. (Gallo KA, Johnson GL, Nat Rev Mol Cell Biol. 2002;3:663–72) We explored the role of MLK3 in HNSCC as a possible therapeutic target. Methods: The requirement of MLK3 for cell proliferation and survival of HNSCC cell lines UM-SCC-38 and -47 (HPV+) (obtained from TE Carey, U Michigan) was investigated using RNA interference (siRNA) and MLK3 inhibitor K252a to inhibit the expression and activity of MLK3. Cells were also exposed to EGFR inhibitor Compound 56 at various concentrations. Proliferation was assessed with MTT after 72 h exposure. The effect of MLK3 inhibition on relevant cell signaling pathways was assessed by immunoblotting with activation-specific phosphoantibodies directed against MAPKs, the prosurvival kinase Akt and apoptotic proteins. Results: MLK3 is overexpressed in malignant HNSCC cell lines compared to normal tonsil lysate, and its expression can be inhibited by siRNA or K 252a. Inhibition of MLK3 expression is associated with downregulation of phospho-Akt and with decreased proliferation. Compound 56 inhibits proliferation at lower concentrations in HPV+ cell line UM-SCC-47 (10 microM) compared with UM-SCC-38 (25 microM), inhibits expression of pErk, and decreases expression of pAkt. Combining siRNA or K252a and compound 56 showed less pAkt expression and increased apoptosis (caspase 3 or PARP cleavage) compared with compound 56 alone. Conclusions: MLK3 may have a role in avoiding apoptosis in HNSCC cells. Its inhibition may enhance the effects of EGFR inhibition in HNSCC. No significant financial relationships to disclose.