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Results: 1 to 10 of 134

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The Pan-Cancer Landscape of Coamplification of the Tyrosine Kinases KIT, KDR, and PDGFRA.
Disel U, Madison R, Abhishek K, Chung JH, Trabucco SE, Matos AO, Frampton GM, Albacker LA, Reddy V, Karadurmus N, Benson A, Webster J, Paydas S, Cabanillas R, Nangia C, Ozturk MA, Millis SZ, Pal SK, Wilky B, Sokol ES, Gay LM, Soman S, Ganesan S, Janeway K, Stephens PJ, Zhu VW, Ou SI, Lovly CM, Gounder M, Schrock AB, Ross JS, Miller VA, Klempner SJ, Ali SM
(2020) Oncologist 25: e39-e47
MeSH Terms: Adolescent, Adult, Aged, Aged, 80 and over, Child, Child, Preschool, Gene Amplification, Humans, Middle Aged, Neoplasms, Receptor Protein-Tyrosine Kinases, Receptor, Platelet-Derived Growth Factor alpha, Vascular Endothelial Growth Factor Receptor-2, Young Adult
Show Abstract · Added September 10, 2020
PURPOSE - Amplifications of receptor tyrosine kinases (RTKS) are therapeutic targets in multiple tumor types (e.g. HER2 in breast cancer), and amplification of the chromosome 4 segment harboring the three RTKs KIT, PDGFRA, and KDR (4q12amp) may be similarly targetable. The presence of 4q12amp has been sporadically reported in small tumor specific series but a large-scale analysis is lacking. We assess the pan-cancer landscape of 4q12amp and provide early clinical support for the feasibility of targeting this amplicon.
EXPERIMENTAL DESIGN - Tumor specimens from 132,872 patients with advanced cancer were assayed with hybrid capture based comprehensive genomic profiling which assays 186-315 genes for all classes of genomic alterations, including amplifications. Baseline demographic data were abstracted, and presence of 4q12amp was defined as 6 or more copies of KIT/KDR/PDGFRA. Concurrent alterations and treatment outcomes with matched therapies were explored in a subset of cases.
RESULTS - Overall 0.65% of cases harbored 4q12amp at a median copy number of 10 (range 6-344). Among cancers with >100 cases in this series, glioblastomas, angiosarcomas, and osteosarcomas were enriched for 4q12amp at 4.7%, 4.8%, and 6.4%, respectively (all p < 0.001), giving an overall sarcoma (n = 6,885) incidence of 1.9%. Among 99 pulmonary adenocarcinoma cases harboring 4q12amp, 50 (50%) lacked any other known driver of NSLCC. Four index cases plus a previously reported case on treatment with empirical TKIs monotherapy had stable disease on average exceeding 20 months.
CONCLUSION - We define 4q12amp as a significant event across the pan-cancer landscape, comparable to known pan-cancer targets such as NTRK and microsatellite instability, with notable enrichment in several cancers such as osteosarcoma where standard treatment is limited. The responses to available TKIs observed in index cases strongly suggest 4q12amp is a druggable oncogenic target across cancers that warrants a focused drug development strategy.
IMPLICATIONS FOR PRACTICE - Coamplification of the receptor tyrosine kinases (rtks) KIT/KDR/PDGFRA (4q12amp) is present broadly across cancers (0.65%), with enrichment in osteosarcoma and gliomas. Evidence for this amplicon having an oncogenic role is the mutual exclusivity of 4q12amp to other known drivers in 50% of pulmonary adenocarcinoma cases. Furthermore, preliminary clinical evidence for driver status comes from four index cases of patients empirically treated with commercially available tyrosine kinase inhibitors with activity against KIT/KDR/PDGFRA who had stable disease for 20 months on average. The sum of these lines of evidence suggests further clinical and preclinical investigation of 4q12amp is warranted as the possible basis for a pan-cancer drug development strategy.
© 2019 The Authors. The Oncologist published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.
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14 MeSH Terms
Variable Response to ALK Inhibitors in NSCLC with a Novel MYT1L-ALK Fusion.
Tsou TC, Gowen K, Ali SM, Miller VA, Schrock AB, Lovly CM, Reckamp KL
(2019) J Thorac Oncol 14: e29-e30
MeSH Terms: Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, Nerve Tissue Proteins, Protein Kinase Inhibitors, Receptor Protein-Tyrosine Kinases, Transcription Factors
Added September 10, 2020
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AXL Mediates Esophageal Adenocarcinoma Cell Invasion through Regulation of Extracellular Acidification and Lysosome Trafficking.
Maacha S, Hong J, von Lersner A, Zijlstra A, Belkhiri A
(2018) Neoplasia 20: 1008-1022
MeSH Terms: Adenocarcinoma, Animals, Benzocycloheptenes, Biological Transport, Cathepsin B, Cell Line, Tumor, Chick Embryo, Chorioallantoic Membrane, Epithelial-Mesenchymal Transition, Esophageal Neoplasms, Gene Expression Regulation, Neoplastic, Humans, Hydrogen-Ion Concentration, Lactates, Lysosomes, Monocarboxylic Acid Transporters, Proto-Oncogene Proteins, Receptor Protein-Tyrosine Kinases, Symporters, Triazoles
Show Abstract · Added April 10, 2019
Esophageal adenocarcinoma (EAC) is a highly aggressive malignancy that is characterized by resistance to chemotherapy and a poor clinical outcome. The overexpression of the receptor tyrosine kinase AXL is frequently associated with unfavorable prognosis in EAC. Although it is well documented that AXL mediates cancer cell invasion as a downstream effector of epithelial-to-mesenchymal transition, the precise molecular mechanism underlying this process is not completely understood. Herein, we demonstrate for the first time that AXL mediates cell invasion through the regulation of lysosomes peripheral distribution and cathepsin B secretion in EAC cell lines. Furthermore, we show that AXL-dependent peripheral distribution of lysosomes and cell invasion are mediated by extracellular acidification, which is potentiated by AXL-induced secretion of lactate through AKT-NF-κB-dependent MCT-1 regulation. Our novel mechanistic findings support future clinical studies to evaluate the therapeutic potential of the AXL inhibitor R428 (BGB324) in highly invasive EAC.
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
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Mechanisms of receptor tyrosine kinase activation in cancer.
Du Z, Lovly CM
(2018) Mol Cancer 17: 58
MeSH Terms: Animals, Cell Transformation, Neoplastic, Enzyme Activation, Gene Expression Regulation, Neoplastic, Humans, Ligands, Molecular Targeted Therapy, Mutation, Neoplasms, Phosphorylation, Protein Binding, Protein Interaction Domains and Motifs, Protein Kinase Inhibitors, Protein Multimerization, Receptor Protein-Tyrosine Kinases, Signal Transduction
Show Abstract · Added September 10, 2020
Receptor tyrosine kinases (RTKs) play an important role in a variety of cellular processes including growth, motility, differentiation, and metabolism. As such, dysregulation of RTK signaling leads to an assortment of human diseases, most notably, cancers. Recent large-scale genomic studies have revealed the presence of various alterations in the genes encoding RTKs such as EGFR, HER2/ErbB2, and MET, amongst many others. Abnormal RTK activation in human cancers is mediated by four principal mechanisms: gain-of-function mutations, genomic amplification, chromosomal rearrangements, and / or autocrine activation. In this manuscript, we review the processes whereby RTKs are activated under normal physiological conditions and discuss several mechanisms whereby RTKs can be aberrantly activated in human cancers. Understanding of these mechanisms has important implications for selection of anti-cancer therapies.
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Managing Resistance to EFGR- and ALK-Targeted Therapies.
Lovly CM, Iyengar P, Gainor JF
(2017) Am Soc Clin Oncol Educ Book 37: 607-618
MeSH Terms: Anaplastic Lymphoma Kinase, Carcinoma, Non-Small-Cell Lung, Drug Resistance, Neoplasm, ErbB Receptors, Humans, Molecular Targeted Therapy, Mutation, Protein Kinase Inhibitors, Receptor Protein-Tyrosine Kinases
Show Abstract · Added September 10, 2020
Targeted therapies have transformed the management of non-small cell lung cancer (NSCLC) and placed an increased emphasis on stratifying patients on the basis of genetic alterations in oncogenic drivers. To date, the best characterized molecular targets in NSCLC are the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK). Despite steady advances in targeted therapies within these molecular subsets, however, acquired resistance to therapy is near universal. Recent preclinical models and translational efforts have provided critical insights into the molecular mechanisms of resistance to EGFR and ALK inhibitors. In this review, we present a framework for understanding resistance to targeted therapies. We also provide overviews of the molecular mechanisms of resistance and strategies to overcome resistance among EGFR-mutant and ALK-rearranged lung cancers. To date, these strategies have centered on the development of novel next-generation inhibitors, rationale combinations, and use of local ablative therapies, such as radiotherapy.
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Expression of receptor-type protein tyrosine phosphatase in developing and adult renal vasculature.
Takahashi K, Kim R, Lauhan C, Park Y, Nguyen NG, Vestweber D, Dominguez MG, Valenzuela DM, Murphy AJ, Yancopoulos GD, Gale NW, Takahashi T
(2017) PLoS One 12: e0177192
MeSH Terms: Animals, Endothelium, Vascular, Kidney, Mice, Phosphorylation, Promoter Regions, Genetic, Protein Tyrosine Phosphatases, Receptor Protein-Tyrosine Kinases
Show Abstract · Added April 6, 2018
Renal vascular development is a coordinated process that requires ordered endothelial cell proliferation, migration, intercellular adhesion, and morphogenesis. In recent decades, studies have defined the pivotal role of endothelial receptor tyrosine kinases (RPTKs) in the development and maintenance of renal vasculature. However, the expression and the role of receptor tyrosine phosphatases (RPTPs) in renal endothelium are poorly understood, though coupled and counterbalancing roles of RPTKs and RPTPs are well defined in other systems. In this study, we evaluated the promoter activity and immunolocalization of two endothelial RPTPs, VE-PTP and PTPμ, in developing and adult renal vasculature using the heterozygous LacZ knock-in mice and specific antibodies. In adult kidneys, both VE-PTP and PTPμ were expressed in the endothelium of arterial, glomerular, and medullary vessels, while their expression was highly limited in peritubular capillaries and venous endothelium. VE-PTP and PTPμ promoter activity was also observed in medullary tubular segments in adult kidneys. In embryonic (E12.5, E13.5, E15.5, E17.5) and postnatal (P0, P3, P7) kidneys, these RPTPs were expressed in ingrowing renal arteries, developing glomerular microvasculature (as early as the S-shaped stage), and medullary vessels. Their expression became more evident as the vasculatures matured. Peritubular capillary expression of VE-PTP was also noted in embryonic and postnatal kidneys. Compared to VE-PTP, PTPμ immunoreactivity was relatively limited in embryonic and neonatal renal vasculature and evident immunoreactivity was observed from the P3 stage. These findings indicate 1) VE-PTP and PTPμ are expressed in endothelium of arterial, glomerular, and medullary renal vasculature, 2) their expression increases as renal vascular development proceeds, suggesting that these RPTPs play a role in maturation and maintenance of these vasculatures, and 3) peritubular capillary VE-PTP expression is down-regulated in adult kidneys, suggesting a role of VE-PTP in the development of peritubular capillaries.
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Cracking the Code of Resistance across Multiple Lines of ALK Inhibitor Therapy in Lung Cancer.
Qiao H, Lovly CM
(2016) Cancer Discov 6: 1084-1086
MeSH Terms: Carcinoma, Non-Small-Cell Lung, Drug Resistance, Neoplasm, Humans, Lung Neoplasms, Protein Kinase Inhibitors, Pyrazoles, Pyridines, Receptor Protein-Tyrosine Kinases
Show Abstract · Added September 10, 2020
In the setting of recent exciting clinical results and numerous ongoing trials, Gainor and colleagues explored mechanisms of acquired resistance to first- and second-generation ALK inhibitors in ALK-rearranged non-small cell lung cancer and found that an increased frequency and distinct spectrums of resistance mutations emerged with the more potent second-generation inhibitors. Their findings have important and immediate clinical implications as the resistance mutations detected impart differential sensitivities to available ALK inhibitors, thereby highlighting the need for sequential biopsies with molecular testing to determine the most effective treatment strategy upon disease progression. Cancer Discov; 6(10); 1084-6. ©2016 AACRSee related article by Gainor et al., p. 1118.
©2016 American Association for Cancer Research.
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Diverse, Biologically Relevant, and Targetable Gene Rearrangements in Triple-Negative Breast Cancer and Other Malignancies.
Shaver TM, Lehmann BD, Beeler JS, Li CI, Li Z, Jin H, Stricker TP, Shyr Y, Pietenpol JA
(2016) Cancer Res 76: 4850-60
MeSH Terms: Algorithms, Cell Line, Tumor, Female, Gene Expression Profiling, Gene Rearrangement, Humans, Immunoblotting, Neoplasms, Oncogene Proteins, Fusion, Polymerase Chain Reaction, Proto-Oncogene Proteins, Receptor Protein-Tyrosine Kinases, Triple Negative Breast Neoplasms, c-Mer Tyrosine Kinase
Show Abstract · Added April 9, 2017
Triple-negative breast cancer (TNBC) and other molecularly heterogeneous malignancies present a significant clinical challenge due to a lack of high-frequency "driver" alterations amenable to therapeutic intervention. These cancers often exhibit genomic instability, resulting in chromosomal rearrangements that affect the structure and expression of protein-coding genes. However, identification of these rearrangements remains technically challenging. Using a newly developed approach that quantitatively predicts gene rearrangements in tumor-derived genetic material, we identified and characterized a novel oncogenic fusion involving the MER proto-oncogene tyrosine kinase (MERTK) and discovered a clinical occurrence and cell line model of the targetable FGFR3-TACC3 fusion in TNBC. Expanding our analysis to other malignancies, we identified a diverse array of novel and known hybrid transcripts, including rearrangements between noncoding regions and clinically relevant genes such as ALK, CSF1R, and CD274/PD-L1 The over 1,000 genetic alterations we identified highlight the importance of considering noncoding gene rearrangement partners, and the targetable gene fusions identified in TNBC demonstrate the need to advance gene fusion detection for molecularly heterogeneous cancers. Cancer Res; 76(16); 4850-60. ©2016 AACR.
©2016 American Association for Cancer Research.
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Tyrosine Kinase Signaling in Clear Cell and Papillary Renal Cell Carcinoma Revealed by Mass Spectrometry-Based Phosphotyrosine Proteomics.
Haake SM, Li J, Bai Y, Kinose F, Fang B, Welsh EA, Zent R, Dhillon J, Pow-Sang JM, Chen YA, Koomen JM, Rathmell WK, Fishman M, Haura EB
(2016) Clin Cancer Res 22: 5605-5616
MeSH Terms: Carcinoma, Papillary, Carcinoma, Renal Cell, Cell Line, Tumor, Cell Survival, ErbB Receptors, Extracellular Matrix, Humans, Kidney Neoplasms, Mass Spectrometry, Phosphorylation, Phosphotyrosine, Protein Kinase Inhibitors, Protein-Tyrosine Kinases, Proteomics, Receptor Protein-Tyrosine Kinases, Signal Transduction, Tyrosine
Show Abstract · Added August 8, 2016
PURPOSE - Targeted therapies in renal cell carcinoma (RCC) are limited by acquired resistance. Novel therapeutic targets are needed to combat resistance and, ideally, target the unique biology of RCC subtypes.
EXPERIMENTAL DESIGN - Tyrosine kinases provide critical oncogenic signaling and their inhibition has significantly impacted cancer care. To describe a landscape of tyrosine kinase activity in RCC that could inform novel therapeutic strategies, we performed a mass spectrometry-based system-wide survey of tyrosine phosphorylation in 10 RCC cell lines as well as 15 clear cell and 15 papillary RCC human tumors. To prioritize identified tyrosine kinases for further analysis, a 63 tyrosine kinase inhibitor (TKI) drug screen was performed.
RESULTS - Among the cell lines, 28 unique tyrosine phosphosites were identified across 19 kinases and phosphatases including EGFR, MET, JAK2, and FAK in nearly all samples. Multiple FAK TKIs decreased cell viability by at least 50% and inhibited RCC cell line adhesion, invasion, and proliferation. Among the tumors, 49 unique tyrosine phosphosites were identified across 44 kinases and phosphatases. FAK pY576/7 was found in all tumors and many cell lines, whereas DDR1 pY792/6 was preferentially enriched in the papillary RCC tumors. Both tyrosine kinases are capable of transmitting signals from the extracellular matrix and emerged as novel RCC therapeutic targets.
CONCLUSIONS - Tyrosine kinase profiling informs novel therapeutic strategies in RCC and highlights the unique biology among kidney cancer subtypes. Clin Cancer Res; 22(22); 5605-16. ©2016 AACR.
©2016 American Association for Cancer Research.
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Histology-Specific Uses of Tyrosine Kinase Inhibitors in Non-gastrointestinal Stromal Tumor Sarcomas.
Sethi TK, Keedy VL
(2016) Curr Treat Options Oncol 17: 11
MeSH Terms: Antineoplastic Agents, Bone Neoplasms, Gastrointestinal Stromal Tumors, Humans, Protein Kinase Inhibitors, Protein-Tyrosine Kinases, Receptor Protein-Tyrosine Kinases, Sarcoma, Signal Transduction
Show Abstract · Added March 16, 2016
OPINION STATEMENT - Adult sarcomas, especially those with metastatic or unresectable disease, have limited treatment options. Traditional chemotherapeutic options have been limited by poor response rates in patients with advanced sarcomas. The important clinical question is whether the success of targeted therapy in GIST can be extended to other sarcomas and also if preclinical data describing targets across this heterogeneous group of cancers can be translated to clinical efficacy of known and upcoming target specific agents. Multi-targeted tyrosine kinase inhibitors (TKI) such as pazopanib, sorafenib, sunutinib, cediranib have shown benefits across various histologies of soft tissue sarcoma as well as bone sarcomas. The efficacy of imatinib in Dermatofibrosarcoma Protruberans; sunitinib and cediranib in alveolar soft part sarcoma; and sorafenib and imatinib in chordomas have provided a treatment option of these rare tumors where no effective options existed. TKIs are being tested in combination with chemotherapy as well as radiation to improve response. Although traditional RECIST criteria may not adequately reflect response to these targeted agents, the studies have shown promise for the efficacy of TKIs across the spectrum of sarcomas. The integration of biomarker studies with clinical trials may help further identify responders beyond that defined by histology. With the current data, TKIs are being used both as first-line treatment and beyond in non-GIST sarcomas.
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9 MeSH Terms