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https://www.readbyqxmd.com/read/28506408/genetics-of-medullary-thyroid-cancer-an-overview
#1
REVIEW
Giacomo Accardo, Giovanni Conzo, Daniela Esposito, Claudio Gambardella, Marco Mazzella, Filomena Castaldo, Carlo Di Donna, Andrea Polistena, Nicola Avenia, Vittorio Colantuoni, Dario Giugliano, Daniela Pasquali
Medullary thyroid carcinoma (MTC) represents 3-5% of thyroid cancers. 75% is sporadic and 25% is the dominant component of the hereditary multiple endocrine neoplasia (MEN) type 2 syndromes. Three different subtypes of MEN2, such as MEN2A, MEN2B, and Familial MTC (FMTC) have been defined, based on presence or absence of hyperparathyroidism, pheocromocytoma and characteristic clinical features. Mutations of the RET proto-oncogene are implicated in the pathogenesis of MTC, but there are many other mutational patterns involved...
May 2017: International Journal of Surgery
https://www.readbyqxmd.com/read/28502721/met-exon-14-skipping-mutations-in-lung-adenocarcinoma-clinicopathologic-implications-and-prognostic-values
#2
Geun Dong Lee, Seung Eun Lee, Doo-Yi Oh, Dan-Bi Yu, Hae Min Jeong, Jooseok Kim, Sungyoul Hong, Hun Soon Jung, Ensel Oh, Ji-Young Song, Mi-Sook Lee, Mingi Kim, Kyungsoo Jung, Jhingook Kim, Young Kee Shin, Yoon-La Choi, Hyeong Ryul Kim
INTRODUCTION: Response to MET inhibitors in non-small cell lung cancer with MET exon 14 (METex14) skipping has fueled molecular screening efforts and search for optimal therapies. However, further work is needed to refine the clinicopathologic and prognostic implications of METex14 skipping METHODS: Among 795 East-Asian patients who underwent surgery for non-small cell lung cancer, we screened 45 patients with quintuple-negative (EGFR-/KRAS-/ALK-/ROS1-/RET-) lung adenocarcinomas using RT-PCR, and found 17 patients (37...
May 10, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/28500237/resistance-to-ret-inhibition-in-ret-rearranged-nsclc-is-mediated-by-reactivation-of-ras-mapk-signaling
#3
Sarah K Nelson-Taylor, Anh T Le, Minjae Yoo, Laura Schubert, Katie M Mishall, Andrea Doak, Marileila Varella-Garcia, Aik-Choon Tan, Robert C Doebele
Oncogenic rearrangements in RET are present in 1-2% of lung adenocarcinoma (LAD) patients. Ponatinib is a multi-kinase inhibitor with low-nanomolar potency against the RET kinase domain. Here, we demonstrate that ponatinib exhibits potent anti-proliferative activity in RET fusion positive LC-2/ad LAD cells and inhibits phosphorylation of the RET fusion protein and signaling through ERK1/2 and AKT. Using distinct dose-escalation strategies, two ponatinib-resistant LC-2/ad cell lines, PR1 and PR2, were derived...
May 12, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28498409/demonstration-of-a-potent-ret-transcriptional-inhibitor-for-the-treatment-of-medullary-thyroid-carcinoma-based-on-an-ellipticine-derivative
#4
Vishnu Muthuraj Kumarasamy, Daekyu Sun
Dominant-activating mutations in the RET (rearranged during transfection) proto-oncogene, which encodes a receptor tyrosine kinase, is often associated with the development of medullary thyroid carcinoma (MTC). The proximal promoter region of the RET gene consists of a guanine-rich sequence containing five runs of three consecutive guanine residues that serve as the binding site for transcriptional factors. As we have recently shown, this stretch of nucleotides in the promoter region is highly dynamic in nature and tend to form non-B DNA secondary structures called G-quadruplexes, which suppress the transcription of the RET gene...
May 11, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28476040/efficacy-of-a-hsp90-inhibitor-ganetespib-in-preclinical-thyroid-cancer-models
#5
Shu-Fu Lin, Jen-Der Lin, Chuen Hsueh, Ting-Chao Chou, Chun-Nan Yeh, Ming-Huang Chen, Richard J Wong
Heat shock protein 90 is a molecular chaperon that maintains the correct folding and function of multiple client proteins. The inhibition of heat shock protein 90, which leads to the simultaneous degradation of multiple proteins involved in oncogenic signaling pathways, has revealed an innovative strategy to treat a variety of cancer types. We evaluated the therapeutic effects of ganetespib, a heat shock protein 90 inhibitor, in treating thyroid cancer. Ganetespib effectively inhibited cell proliferation in a dose-dependent manner in eight cell lines originating from four major histologic types of thyroid cancer (papillary, follicular, anaplastic and medullary)...
April 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28464908/a-phase-i-study-of-lapatinib-in-combination-with-foretinib-a-c-met-axl-and-vascular-endothelial-growth-factor-receptor-inhibitor-in-human-epidermal-growth-factor-receptor-2-her-2-positive-metastatic-breast-cancer
#6
Stephen K Chia, Susan L Ellard, Mihaela Mates, Stephen Welch, Catalin Mihalcioiu, Wilson H Miller, Karen Gelmon, Caroline Lohrisch, Vikaash Kumar, Sara Taylor, Linda Hagerman, Rachel Goodwin, Tao Wang, Shingo Sakashita, Ming S Tsao, Elizabeth Eisenhauer, Penelope Bradbury
BACKGROUND: The mechanisms of resistance to anti-human epidermal growth factor receptor 2 (HER 2) therapies are unclear but may include the tyrosine-protein kinase Met (c-Met), vascular endothelial growth factor (VEGF) and AXL pathways. Foretinib is an inhibitor of c-Met, VEGF receptor 2 (VEGFR-2), platelet-derived growth factor receptor beta (PDGFRB), AXL, Fms-like tyrosine kinase 3 (FLT3), angiopoiten receptor (TIE-2), RET and RON kinases. This phase Ib study sought to establish the associated toxicities, pharmacokinetics (PK) and recommended phase II doses (RP2D) of foretinib and lapatinib in a cohort of HER-2-positive patients with metastatic breast cancer (MBC)...
May 2, 2017: Breast Cancer Research: BCR
https://www.readbyqxmd.com/read/28460442/egfr-mediates-activation-of-ret-in-lung-adenocarcinoma-with-neuroendocrine-differentiation-characterized-by-ascl1-expression
#7
Kaustubh Bhinge, Lin Yang, Simone Terra, Aqsa Nasir, Prasuna Muppa, Marie Christine Aubry, Joanne Yi, Nafiseh Janaki, Irina V Kovtun, Stephen J Murphy, Geoffrey Halling, Hamed Rahi, Aaron Mansfield, Mariza de Andrade, Ping Yang, George Vasmatzis, Tobias Peikert, Farhad Kosari
Achaete-scute homolog 1 (ASCL1) is a neuroendocrine transcription factor specifically expressed in 10-20% of lung adenocarcinomas (AD) with neuroendocrine (NE) differentiation (NED). ASCL1 functions as an upstream regulator of the RET oncogene in AD with high ASCL1 expression (A+AD). RET is a receptor tyrosine kinase with two main human isoforms; RET9 (short) and RET51 (long). We found that elevated expression of RET51 associated mRNA was highly predictive of poor survival in stage-1 A+AD (p=0.0057). Functional studies highlighted the role of RET in promoting invasive properties of A+AD cells...
April 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28447912/targeting-ret-in-patients-with-ret-rearranged-lung-cancers-results-from-the-global-multicenter-ret-registry
#8
Oliver Gautschi, Julie Milia, Thomas Filleron, Juergen Wolf, David P Carbone, Dwight Owen, Ross Camidge, Vignhesh Narayanan, Robert C Doebele, Benjamin Besse, Jordi Remon-Masip, Pasi A Janne, Mark M Awad, Nir Peled, Chul-Cho Byoung, Daniel D Karp, Michael Van Den Heuvel, Heather A Wakelee, Joel W Neal, Tony S K Mok, James C H Yang, Sai-Hong Ignatius Ou, Georg Pall, Patrizia Froesch, Gérard Zalcman, David R Gandara, Jonathan W Riess, Vamsidhar Velcheti, Kristin Zeidler, Joachim Diebold, Martin Früh, Sebastian Michels, Isabelle Monnet, Sanjay Popat, Rafael Rosell, Niki Karachaliou, Sacha I Rothschild, Jin-Yuan Shih, Arne Warth, Thomas Muley, Florian Cabillic, Julien Mazières, Alexander Drilon
Purpose In addition to prospective trials for non-small-cell lung cancers (NSCLCs) that are driven by less common genomic alterations, registries provide complementary information on patient response to targeted therapies. Here, we present the results of an international registry of patients with RET-rearranged NSCLCs, providing the largest data set, to our knowledge, on outcomes of RET-directed therapy thus far. Methods A global, multicenter network of thoracic oncologists identified patients with pathologically confirmed NSCLC that harbored a RET rearrangement...
May 1, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28435794/cushing-disease-in-a-patient-with-multiple-endocrine-neoplasia-type-2b
#9
Kannan Kasturi, Lucas Fernandes, Martha Quezado, Mary Eid, Leigh Marcus, Prashant Chittiboina, Mark Rappaport, Constantine A Stratakis, Brigitte Widemann, Maya Lodish
CONTEXT: Multiple endocrine neoplasia type 2B (MEN2B) is a rare autosomal-dominant cancer syndrome characterized in part by metastatic medullary thyroid cancer (MTC) and pheochromocytoma. Cushing disease is a rare cause of endogenous hypercortisolism in children. CASE DESCRIPTION: We describe a 21-year-old African-American male who was diagnosed at age 10 with an ACTH-secreting pituitary microadenoma. At age 16 he developed medullary thyroid cancer and was found to have multiple endocrine neoplasia type 2B with the characteristic M918T mutation of the RET proto-oncogene...
June 2017: J Clin Transl Endocrinol Case Rep
https://www.readbyqxmd.com/read/28428274/egfr-mediates-responses-to-small-molecule-drugs-targeting-oncogenic-fusion-kinases
#10
Aria Vaishnavi, Laura Schubert, Uwe Rix, Lindsay A Marek, Anh T Le, Stephen Keysar, Magdalena J Glogowska, Matthew A Smith, Severine L Kako, Natalia J Sumi, Kurtis D Davies, Kathryn E Ware, Marileila Varella-Garcia, Eric B Haura, Antonio Jimeno, Lynn E Heasley, Dara L Aisner, Robert C Doebele
Oncogenic kinase fusions of ALK, ROS1, RET and NTRK1 act as drivers in human lung and other cancers. Residual tumor burden following treatment of ALK or ROS1+ lung cancer patients with oncogene-targeted therapy ultimately enables the emergence of drug-resistant clones, limiting the long-term effectiveness of these therapies. To determine the signaling mechanisms underlying incomplete tumor cell killing in oncogene-addicted cancer cells, we investigated the role of EGFR signaling in drug-naive cancer cells harboring these oncogene fusions...
April 20, 2017: Cancer Research
https://www.readbyqxmd.com/read/28427247/molecular-testing-of-lung-cancers
#11
Hyo Sup Shim, Yoon-La Choi, Lucia Kim, Sunhee Chang, Wan-Seop Kim, Mee Sook Roh, Tae-Jung Kim, Seung Yeon Ha, Jin-Haeng Chung, Se Jin Jang, Geon Kook Lee
Targeted therapies guided by molecular diagnostics have become a standard treatment of lung cancer. Epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements are currently used as the best predictive biomarkers for EGFR tyrosine kinase inhibitors and ALK inhibitors, respectively. Besides EGFR and ALK, the list of druggable genetic alterations has been growing, including ROS1 rearrangements, RET rearrangements, and MET alterations. In this situation, pathologists should carefully manage clinical samples for molecular testing and should do their best to quickly and accurately identify patients who will benefit from precision therapeutics...
April 21, 2017: Journal of Pathology and Translational Medicine
https://www.readbyqxmd.com/read/28423638/her-inhibitor-promotes-braf-mek-inhibitor-induced-redifferentiation-in-papillary-thyroid-cancer-harboring-brafv600e
#12
Lingxiao Cheng, Yuchen Jin, Min Liu, Maomei Ruan, Libo Chen
Redifferentiation therapy with BRAF/MEK inhibitors to facilitate treatment with radioiodine represents a good choice for radioiodine-refractory differentiated thyroid carcinoma, but recent initial clinical outcomes were modest. MAPK rebound caused by BRAF/MEK inhibitors-induced activation of HER2/HER3 is a resistance mechanism, and combination with HER inhibitor to prevent MAPK rebound may sensitize BRAFV600E-mutant thyroid cancer cells to redifferentiation therapy. To evaluate if inhibiting both BRAF/MEK and HER can produce stronger redifferetiation effect, we tested the effects of BRAF/MEK inhibitor dabrafenib/selumetinib alone or in combination with HER inhibitor lapatinib on the expression and function of iodine- and glucose-handling genes in BRAFV600E-positive BCPAP and K1 cells, using BHP 2-7 cells harboring RET/PTC1 rearrangement as control...
March 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/28423517/next-generation-sequencing-of-extraskeletal-myxoid-chondrosarcoma
#13
Elizabeth J Davis, Yi-Mi Wu, Dan Robinson, Scott M Schuetze, Laurence H Baker, Jyoti Athanikar, Xuhong Cao, Lakshmi P Kunju, Arul M Chinnaiyan, Rashmi Chugh
Extraskeletal myxoid chondrosarcoma (EMC) is an indolent translocation-associated soft tissue sarcoma with a high propensity for metastases. Using a clinical sequencing approach, we genomically profiled patients with metastatic EMC to elucidate the molecular biology and identify potentially actionable mutations. We also evaluated potential predictive factors of benefit to sunitinib, a multi-targeted tyrosine kinase inhibitor with reported activity in a subset of EMC patients. Between January 31, 2012 and April 15, 2016, six patients with EMC participated in the clinical sequencing research study...
March 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28415793/clinical-framework-for-next-generation-sequencing-based-analysis-of-treatment-predictive-mutations-and-multiplexed-gene-fusion-detection-in-non-small-cell-lung-cancer
#14
Kajsa Ericson Lindquist, Anna Karlsson, Per Levéen, Hans Brunnström, Christel Reuterswärd, Karolina Holm, Mats Jönsson, Karin Annersten, Frida Rosengren, Karin Jirström, Jaroslaw Kosieradzki, Lars Ek, Åke Borg, Maria Planck, Göran Jönsson, Johan Staaf
Precision medicine requires accurate multi-gene clinical diagnostics. We describe the implementation of an Illumina TruSight Tumor (TST) clinical NGS diagnostic framework and parallel validation of a NanoString RNA-based ALK, RET, and ROS1 gene fusion assay for combined analysis of treatment predictive alterations in non-small cell lung cancer (NSCLC) in a regional healthcare region of Sweden (Scandinavia). The TST panel was clinically validated in 81 tumors (99% hotspot mutation concordance), after which 533 consecutive NSCLCs were collected during one-year of routine clinical analysis in the healthcare region (~90% advanced stage patients)...
March 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28404587/cic-dux4-induces-small-round-cell-sarcomas-distinct-from-ewing-sarcoma
#15
Toyoki Yoshimoto, Miwa Tanaka, Mizuki Homme, Yukari Yamazaki, Yutaka Takazawa, Cristina R Antonescu, Takuro Nakamura
CIC-DUX4 sarcoma (CDS) or CIC-rearranged sarcoma is a  subcategory of small round cell sarcoma resembling the morphological phenotypes of Ewing sarcoma (ES). Hoever, recent clinicopathologic and molecular genetic analyses indicate that CDS is an independent disease entity from ES. Few ancillary markers have been used in the differential diagnosis of CDS, and additional CDS-specific biomarkers are needed for more definitive classification. Here we report the generation of an ex vivo mouse model for CDS by transducing embryonic mesenchymal cells (eMC) with human CIC-DUX4 cDNA...
April 12, 2017: Cancer Research
https://www.readbyqxmd.com/read/28404375/synthesis-and-structure-activity-relationship-study-of-pyrazolo-3-4-d-pyrimidines-as-tyrosine-kinase-ret-inhibitors
#16
Chengyan Wang, Hongchun Liu, Zilan Song, Yinchun Ji, Li Xing, Xia Peng, Xisheng Wang, Jing Ai, Meiyu Geng, Ao Zhang
Three series of pyrazolo[3,4-d]pyrimidine derivatives were synthesized and evaluated as RET kinase inhibitors. Compounds 23a and 23c were identified to show significant activity both in the biochemical and the BaF3/CCDC6-RET cell assays. Compound 23c was found to significantly inhibit RET phosphorylation and down-stream signaling in BaF3/CCDC6-RET cells, confirming its potent cellular RET-targeting profile. Different from other RET inhibitors with equal potency against KDR that associated with severe toxicity, 23c did not show significant KDR-inhibition even at the concentration of 1μM...
March 31, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28350094/routine-genetic-testing-of-lung-cancer-specimens-derived-from-surgery-bronchoscopy-and-fluid-aspiration-by-next-generation-sequencing
#17
Gou Yamamoto, Mari Kikuchi, Shiho Kobayashi, Yoshiko Arai, Kenji Fujiyoshi, Tomokazu Wakatsuki, Miho Kakuta, Yuki Yamane, Yoshihito Iijima, Hideaki Mizutani, Yuki Nakajima, Junko Sudo, Hiroyasu Kinoshita, Futoshi Kurimoto, Hirohiko Akiyama, Hidetaka Uramoto, Hiroshi Sakai, Yoshito Akagi, Kiwamu Akagi
After the development of EGFR tyrosine kinase inhibitors (TKIs), genetic testing of EGFR became required for effective treatment of lung cancer. Initially, the testing was conducted separately for each mutated region. However, many EGFR mutations have since been identified that determine the efficacy of EGFR-TKIs. Therefore, genetic testing of EGFR by next generation sequencing (NGS) may be a suitable strategy for lung cancer. Here we examined the applicability of the NGS method in regard to sensitivity, time and cost...
May 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28336808/potent-dual-bet-bromodomain-kinase-inhibitors-as-value-added-multi-targeted-chemical-probes-and-cancer-therapeutics
#18
Stuart W Ember, Que T Lambert, Norbert Berndt, Steven Gunawan, Muhammad Ayaz, Marilena Tauro, Jin-Yi Zhu, Paula J Cranfill, Patricia Greninger, Conor C Lynch, Cyril H Benes, Harshani R Lawrence, Gary W Reuther, Nicholas J Lawrence, Ernst Schonbrunn
Synergistic action of kinase and BET bromodomain inhibitors in cell killing has been reported for a variety of cancers. Using the chemical scaffold of the JAK2 inhibitor TG101348 we developed and characterized single agents which potently and simultaneously inhibit BRD4 and a specific set of oncogenic tyrosine kinases including JAK2, FLT3, RET, and ROS1. Lead compounds showed on-target inhibition in several blood cancer cell lines and were highly efficacious at inhibiting the growth of hematopoietic progenitor cells from myeloproliferative neoplasm (MPN) patients...
March 23, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28259610/vandetanib-plus-gemcitabine-versus-placebo-plus-gemcitabine-in-locally-advanced-or-metastatic-pancreatic-carcinoma-vip-a-prospective-randomised-double-blind-multicentre-phase-2-trial
#19
Gary Middleton, Daniel H Palmer, William Greenhalf, Paula Ghaneh, Richard Jackson, Trevor Cox, Anthony Evans, Victoria E Shaw, Jonathan Wadsley, Juan W Valle, David Propper, Harpreet Wasan, Stephen Falk, David Cunningham, Fareeda Coxon, Paul Ross, Srinivasan Madhusudan, Nick Wadd, Pippa Corrie, Tamas Hickish, Eithne Costello, Fiona Campbell, Charlotte Rawcliffe, John P Neoptolemos
BACKGROUND: Erlotinib is an EGFR tyrosine kinase inhibitor that has shown a significant but only marginally improved median overall survival when combined with gemcitabine in patients with locally advanced and metastatic pancreatic cancer. Vandetanib is a novel tyrosine kinase inhibitor of VEGFR2, RET, and EGFR, all of which are in involved in the pathogenesis of pancreatic cancer. We investigated the clinical efficacy of vandetanib when used in combination with gemcitabine in patients with advanced pancreatic cancer...
April 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28254765/biological-therapies-in-nonsmall-cell-lung-cancer
#20
REVIEW
Jon Zugazagoitia, Sonia Molina-Pinelo, Fernando Lopez-Rios, Luis Paz-Ares
Biological therapies have improved survival outcomes of advanced-stage nonsmall cell lung cancer (NSCLC). Genotype-directed therapies have changed treatment paradigms of patients with EGFR-mutant and ALK/ROS1-rearranged lung adenocarcinomas, and the list of druggable targets with demonstrated clinical actionability (BRAF, MET, RET, NTRK1 and HER2) continues to expand. Furthermore, we have incrementally understood the mechanisms of cancer immune evasion and foresee ways to effectively circumvent them, particularly at the immune checkpoint level...
March 2017: European Respiratory Journal: Official Journal of the European Society for Clinical Respiratory Physiology
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