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Co-1686

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https://www.readbyqxmd.com/read/27435396/preclinical-comparison-of-osimertinib-with-other-egfr-tkis-in-egfr-mutant-nsclc-brain-metastases-models-and-early-evidence-of-clinical-brain-metastases-activity
#1
Peter Ballard, James W T Yates, Zhenfan Yang, Dong-Wan Kim, James Chih-Hsin Yang, Mireille Cantarini, Kathryn Pickup, Angela Jordan, Mike Hickey, Matthew Grist, Matthew Box, Peter Johnström, Katarina Varnäs, Jonas Malmquist, Kenneth S Thress, Pasi A Jänne, Darren Cross
PURPOSE: Approximately one-third of patients with non-small cell lung cancer (NSCLC) harboring tumors with EGFR-tyrosine kinase inhibitor (TKI)-sensitizing mutations (EGFRm) experience disease progression during treatment due to brain metastases. Despite anecdotal reports of EGFR-TKIs providing benefit in some patients with EGFRm NSCLC brain metastases, there is a clinical need for novel EGFR-TKIs with improved efficacy against brain lesions. EXPERIMENTAL DESIGN: We performed preclinical assessments of brain penetration and activity of osimertinib (AZD9291), an oral, potent, irreversible EGFR-TKI selective for EGFRm and T790M resistance mutations, and other EGFR-TKIs in various animal models of EGFR-mutant NSCLC brain metastases...
October 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27257132/l718q-mutation-as-new-mechanism-of-acquired-resistance-to-azd9291-in-egfr-mutated-nsclc
#2
Melissa Bersanelli, Roberta Minari, Paola Bordi, Letizia Gnetti, Cecilia Bozzetti, Anna Squadrilli, Costanza Anna Maria Lagrasta, Lorena Bottarelli, Ganna Osipova, Enrica Capelletto, Marco Mor, Marcello Tiseo
No abstract text is available yet for this article.
October 2016: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/27252416/heterogeneous-mechanisms-of-primary-and-acquired-resistance-to-third-generation-egfr-inhibitors
#3
Sandra Ortiz-Cuaran, Matthias Scheffler, Dennis Plenker, Llona Dahmen, Andreas H Scheel, Lynnette Fernandez-Cuesta, Lydia Meder, Christine M Lovly, Thorsten Persigehl, Sabine Merkelbach-Bruse, Marc Bos, Sebastian Michels, Rieke Fischer, Kerstin Albus, Katharina König, Hans-Ulrich Schildhaus, Jana Fassunke, Michaela A Ihle, Helen Pasternack, Carina Heydt, Christian Becker, Janine Altmüller, Hongbin Ji, Christian Müller, Alexandra Florin, Johannes M Heuckmann, Peter Nuernberg, Sascha Ansén, Lukas C Heukamp, Johannes Berg, William Pao, Martin Peifer, Reinhard Buettner, Jürgen Wolf, Roman K Thomas, Martin L Sos
PURPOSE: To identify novel mechanisms of resistance to third-generation EGFR inhibitors in patients with lung adenocarcinoma that progressed under therapy with either AZD9291 or rociletinib (CO-1686). EXPERIMENTAL DESIGN: We analyzed tumor biopsies from seven patients obtained before, during, and/or after treatment with AZD9291 or rociletinib (CO-1686). Targeted sequencing and FISH analyses were performed, and the relevance of candidate genes was functionally assessed in in vitro models...
June 1, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/26747242/assessment-of-egfr-mutation-status-in-matched-plasma-and-tumor-tissue-of-nsclc-patients-from-a-phase-i-study-of-rociletinib-co-1686
#4
Chris Karlovich, Jonathan W Goldman, Jong-Mu Sun, Elaina Mann, Lecia V Sequist, Krzysztof Konopa, Wei Wen, Philipp Angenendt, Leora Horn, David Spigel, Jean-Charles Soria, Benjamin Solomon, D Ross Camidge, Shirish Gadgeel, Cloud Paweletz, Lin Wu, Sean Chien, Patrick O'Donnell, Shannon Matheny, Darrin Despain, Lindsey Rolfe, Mitch Raponi, Andrew R Allen, Keunchil Park, Heather Wakelee
PURPOSE: The evaluation of plasma testing for the EGFR resistance mutation T790M in NSCLC patients has not been broadly explored. We investigated the detection of EGFR activating and T790M mutations in matched tumor tissue and plasma, mostly from patients with acquired resistance to first-generation EGFR inhibitors. EXPERIMENTAL DESIGN: Samples were obtained from two studies, an observational study and a phase I trial of rociletinib, a mutant-selective inhibitor of EGFR that targets both activating mutations and T790M...
May 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/26629855/covalent-targeting-of-acquired-cysteines-in-cancer
#5
REVIEW
Marieke Visscher, Michelle R Arkin, Tobias B Dansen
The thiolate side chain of cysteine has a unique functionality that drug hunters and chemical biologists have begun to exploit. For example, targeting cysteine residues in the ATP-binding pockets of kinases with thiol-reactive molecules has afforded increased selectivity and potency to drugs like imbrutinib, which inhibits the oncogene BTK, and CO-1686 and AZD9291 that target oncogenic mutant EGFR. Recently, disulfide libraries and targeted GDP-mimetics have been used to selectively label the G12C oncogenic mutation in KRAS...
February 2016: Current Opinion in Chemical Biology
https://www.readbyqxmd.com/read/26508839/dacomitinib-in-lung-cancer-a-lost-generation-egfr-tyrosine-kinase-inhibitor-from-a-bygone-era
#6
REVIEW
Sai-Hong Ignatius Ou, Ross A Soo
EGFR tyrosine-kinase inhibitors (TKIs) have now been firmly established as the first-line treatment for non-small-cell lung cancer (NSCLC) patients harboring activating EGFR mutations, based on seven prospective randomized Phase III trials. However, despite significantly improved overall response rate and improved median progression-free survival when compared to platinum-doublet chemotherapy, EGFR-mutant NSCLC patients treated with EGFR TKIs invariably progress due to the emergence of acquired resistances, with the gatekeeper T790M mutation accounting for up to 60% of the resistance mechanisms...
2015: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/26275028/targeting-drug-resistance-in-egfr-with-covalent-inhibitors-a-structure-based-design-approach
#7
Julian Engel, André Richters, Matthäus Getlik, Stefano Tomassi, Marina Keul, Martin Termathe, Jonas Lategahn, Christian Becker, Svenja Mayer-Wrangowski, Christian Grütter, Niklas Uhlenbrock, Jasmin Krüll, Niklas Schaumann, Simone Eppmann, Patrick Kibies, Franziska Hoffgaard, Jochen Heil, Sascha Menninger, Sandra Ortiz-Cuaran, Johannes M Heuckmann, Verena Tinnefeld, René P Zahedi, Martin L Sos, Carsten Schultz-Fademrecht, Roman K Thomas, Stefan M Kast, Daniel Rauh
Receptor tyrosine kinases represent one of the prime targets in cancer therapy, as the dysregulation of these elementary transducers of extracellular signals, like the epidermal growth factor receptor (EGFR), contributes to the onset of cancer, such as non-small cell lung cancer (NSCLC). Strong efforts were directed to the development of irreversible inhibitors and led to compound CO-1686, which takes advantage of increased residence time at EGFR by alkylating Cys797 and thereby preventing toxic effects. Here, we present a structure-based approach, rationalized by subsequent computational analysis of conformational ligand ensembles in solution, to design novel and irreversible EGFR inhibitors based on a screening hit that was identified in a phenotype screen of 80 NSCLC cell lines against approximately 1500 compounds...
September 10, 2015: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/26259806/2-4-diarylamino-pyrimidines-as-kinase-inhibitors-co-targeting-igf1r-and-egfr-l%C3%A2-%C3%A2-%C2%B5%C3%A2-r-t%C3%A2-%C3%A2-%C3%A2-m
#8
Shingpan Chan, Kun Han, Rong Qu, Linjiang Tong, Yingjun Li, Zhang Zhang, Huimin Cheng, Xiaoyun Lu, Adam Patterson, Jeff Smaill, Xiaomei Ren, Jian Ding, Hua Xie, Ke Ding
IGF1R amplification was recently implied to be related to the secondary acquired resistance against the 2nd or 3rd generation EGFR inhibitor therapies. We have successfully identified a series of 2,4-diarylamino-pyrimidines as new IGF1R/EGFR(L858R/T790M) co-targeting agents. One of the most promising compounds 8g potently inhibits both kinases with low nanomolar IC50 values, but is significantly less potent in inhibiting the wild type EGFR. The compound also displays a good kinase selectivity profile against a panel of 468 kinases...
October 1, 2015: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/26015408/nf-%C3%AE%C2%BAb-drives-acquired-resistance-to-a-novel-mutant-selective-egfr-inhibitor
#9
Elena Galvani, Jing Sun, Leticia G Leon, Rocco Sciarrillo, Ravi S Narayan, Robert Tjin Tham Sjin, Kwangho Lee, Kadoaki Ohashi, Daniëlle A M Heideman, Roberta R Alfieri, Guus J Heynen, René Bernards, Egbert F Smit, William Pao, Godefridus J Peters, Elisa Giovannetti
The clinical efficacy of EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) harbouring activating EGFR mutations is limited by the emergence of acquired resistance, mostly ascribed to the secondary EGFR-T790M mutation. Selective EGFR-T790M inhibitors have been proposed as a new, extremely relevant therapeutic approach. Here, we demonstrate that the novel irreversible EGFR-TKI CNX-2006, a structural analog of CO-1686, currently tested in a phase-1/2 trial, is active against in vitro and in vivo NSCLC models expressing mutant EGFR, with minimal effect on the wild-type receptor...
December 15, 2015: Oncotarget
https://www.readbyqxmd.com/read/25948633/egfr-mutations-and-resistance-to-irreversible-pyrimidine-based-egfr-inhibitors
#10
Dalia Ercan, Hwan Geun Choi, Cai-Hong Yun, Marzia Capelletti, Ting Xie, Michael J Eck, Nathanael S Gray, Pasi A Jänne
PURPOSE: Mutant selective irreversible pyrimidine-based EGFR kinase inhibitors, including WZ4002, CO-1686, and AZD9291, are effective in preclinical models and in lung cancer patients harboring the EGFR T790M gefitinib/erlotinib resistance mutation. However, little is known about how cancers develop acquired resistance to this class of EGFR inhibitors. We sought to identify and study EGFR mutations that confer resistance to this class of agents. EXPERIMENTAL DESIGN: We performed an N-ethyl-N-nitrosourea (ENU) mutagenesis screen in EGFR-mutant (sensitizing alone or with concurrent EGFR T790M) Ba/F3 cells and selected drug-resistant clones...
September 1, 2015: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/25936890/-tki-resistance-for-t790m-mutation
#11
REVIEW
Hong Wang, Rui Guo, Liyu Zhang
Epidermal growth factor receptor (EGFR) the development of orally activesmall molecule inhibitors for non-small cell lung cancer (NSCLC) provides anew treatment plan. EGFR gene mutation in patients with activation EGFR tyrosine kinase inhibitor (EGFR-TKIs) therapy for the treatment of sensitive, so that a large number of clinical benefit. The first generation of reversible ATP-competitive EGFR-TKIs, gefitinib and erlotinib as first-line, second-line or has the effect of maintenance therapy. Although the initial effect of these drugs have, but most patients will produce drug resistance...
April 2015: Zhongguo Fei Ai za Zhi, Chinese Journal of Lung Cancer
https://www.readbyqxmd.com/read/25923550/rociletinib-in-egfr-mutated-non-small-cell-lung-cancer
#12
RANDOMIZED CONTROLLED TRIAL
Lecia V Sequist, Jean-Charles Soria, Jonathan W Goldman, Heather A Wakelee, Shirish M Gadgeel, Andrea Varga, Vassiliki Papadimitrakopoulou, Benjamin J Solomon, Geoffrey R Oxnard, Rafal Dziadziuszko, Dara L Aisner, Robert C Doebele, Cathy Galasso, Edward B Garon, Rebecca S Heist, Jennifer Logan, Joel W Neal, Melody A Mendenhall, Suzanne Nichols, Zofia Piotrowska, Antoinette J Wozniak, Mitch Raponi, Chris A Karlovich, Sarah Jaw-Tsai, Jeffrey Isaacson, Darrin Despain, Shannon L Matheny, Lindsey Rolfe, Andrew R Allen, D Ross Camidge
BACKGROUND: Non-small-cell lung cancer (NSCLC) with a mutation in the gene encoding epidermal growth factor receptor (EGFR) is sensitive to approved EGFR inhibitors, but resistance develops, mediated by the T790M EGFR mutation in most cases. Rociletinib (CO-1686) is an EGFR inhibitor active in preclinical models of EGFR-mutated NSCLC with or without T790M. METHODS: In this phase 1-2 study, we administered rociletinib to patients with EGFR-mutated NSCLC who had disease progression during previous treatment with an existing EGFR inhibitor...
April 30, 2015: New England Journal of Medicine
https://www.readbyqxmd.com/read/25795814/o10-3rociletinib-an-oral-irreversible-highly-selective-small-molecule-inhibitor-of-mutant-egfr-including-t790m
#13
J-C Soria, L V Sequist, J Goldman, H A Wakelee, J Neal, R Camidge, S Gadgeel, V Papadimitrakopoulou, R Dziadziuszko, Z Piotrowska, A Varga, B J Solomon
BACKGROUND: Rociletinib (CO-1686) is a potent, oral, irreversible inhibitor of mutant EGFR, including the T790M resistance mutation. T790M accounts for 60% of acquired resistance to first and second generation EGFR inhibitors1. We review interim phase 2 data from an ongoing phase 1/2 study (TIGERX; EudraCT 2011-005215-86) in patients with advanced, previously treated, mutant EGFR non small cell lung cancer2. MATERIALS AND METHODS: Eligible patients have advanced EGFR mutant T790M + /- non small cell lung cancer (NSCLC), previous treatment with at least one EGFR inhibitor, ECOG PS 0-1, and adequate organ function...
March 2015: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/25611025/second-and-third-generation-epidermal-growth-factor-receptor-tyrosine-kinase-inhibitors-in-advanced-nonsmall-cell-lung-cancer
#14
REVIEW
Bin-Chi Liao, Chia-Chi Lin, James Chih-Hsin Yang
PURPOSE OF REVIEW: The first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), gefitinib and erlotinib, are effective as first-line treatment of advanced nonsmall cell lung cancer (NSCLC) harboring activating EGFR mutations (deletions in exon 19 and exon 21 L858R mutation). EGFR T790 M resistance mutation (EGFR T790 M) ultimately emerged in most of these patients. The second and third-generation EGFR-TKIs were designed to have more potent inhibition of EGFR and to overcome EGFR T790 M...
March 2015: Current Opinion in Oncology
https://www.readbyqxmd.com/read/25302162/review-of-the-current-targeted-therapies-for-non-small-cell-lung-cancer
#15
REVIEW
Kim-Son H Nguyen, Joel W Neal, Heather Wakelee
The last decade has witnessed the development of oncogene-directed targeted therapies that have significantly changed the treatment of non-small-cell lung cancer (NSCLC). In this paper we review the data demonstrating efficacy of gefitinib, erlotinib, and afatinib, which target the epidermal growth factor receptor (EGFR), and crizotinib which targets anaplastic lymphoma kinase (ALK). We discuss the challenge of acquired resistance to these small-molecular tyrosine kinase inhibitors and review promising agents which may overcome resistance, including the EGFR T790M-targeted agents CO-1686 and AZD9291, and the ALK-targeted agents ceritinib (LDK378), AP26113, alectinib (CH/RO5424802), and others...
October 10, 2014: World Journal of Clinical Oncology
https://www.readbyqxmd.com/read/25296354/epidermal-growth-factor-receptor-egfr-mutations-in-lung-cancer-preclinical-and-clinical-data
#16
REVIEW
S E D C Jorge, S S Kobayashi, D B Costa
Lung cancer leads cancer-related mortality worldwide. Non-small-cell lung cancer (NSCLC), the most prevalent subtype of this recalcitrant cancer, is usually diagnosed at advanced stages, and available systemic therapies are mostly palliative. The probing of the NSCLC kinome has identified numerous nonoverlapping driver genomic events, including epidermal growth factor receptor (EGFR) gene mutations. This review provides a synopsis of preclinical and clinical data on EGFR mutated NSCLC and EGFR tyrosine kinase inhibitors (TKIs)...
November 2014: Brazilian Journal of Medical and Biological Research, Revista Brasileira de Pesquisas Médicas e Biológicas
https://www.readbyqxmd.com/read/25211582/epidermal-growth-factor-receptor-egfr-mutations-in-lung-cancer-preclinical-and-clinical-data
#17
S E D C Jorge, S S Kobayashi, D B Costa
Lung cancer leads cancer-related mortality worldwide. Non-small-cell lung cancer (NSCLC), the most prevalent subtype of this recalcitrant cancer, is usually diagnosed at advanced stages, and available systemic therapies are mostly palliative. The probing of the NSCLC kinome has identified numerous nonoverlapping driver genomic events, including epidermal growth factor receptor (EGFR) gene mutations. This review provides a synopsis of preclinical and clinical data on EGFR mutated NSCLC and EGFR tyrosine kinase inhibitors (TKIs)...
September 5, 2014: Brazilian Journal of Medical and Biological Research, Revista Brasileira de Pesquisas Médicas e Biológicas
https://www.readbyqxmd.com/read/25027951/oral-epidermal-growth-factor-receptor-tyrosine-kinase-inhibitors-for-the-treatment-of-non-small-cell-lung-cancer-comparative-pharmacokinetics-and-drug-drug-interactions
#18
Solange Peters, Stefan Zimmermann, Alex A Adjei
The development of orally active small molecule inhibitors of the epidermal growth factor receptor (EGFR) has led to new treatment options for non-small cell lung cancer (NSCLC). Patients with activating mutations of the EGFR gene show sensitivity to, and clinical benefit from, treatment with EGFR tyrosine kinase inhibitors (EGFR-TKls). First generation reversible ATP-competitive EGFR-TKls, gefitinib and erlotinib, are effective as first, second-line or maintenance therapy. Despite initial benefit, most patients develop resistance within a year, 50-60% of cases being related to the appearance of a T790M gatekeeper mutation...
September 2014: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/24723450/in-vitro-and-in-vivo-characterization-of-irreversible-mutant-selective-egfr-inhibitors-that-are-wild-type-sparing
#19
Robert Tjin Tham Sjin, Kwangho Lee, Annette O Walter, Aleksandr Dubrovskiy, Michael Sheets, Thia St Martin, Matthew T Labenski, Zhendong Zhu, Richland Tester, Russell Karp, Aravind Medikonda, Prasoon Chaturvedi, Yixuan Ren, Henry Haringsma, Jeff Etter, Mitch Raponi, Andrew D Simmons, Thomas C Harding, Deqiang Niu, Mariana Nacht, William F Westlin, Russell C Petter, Andrew Allen, Juswinder Singh
Patients with non-small cell lung carcinoma (NSCLC) with activating mutations in epidermal growth factor receptor (EGFR) initially respond well to the EGFR inhibitors erlotinib and gefitinib. However, all patients relapse because of the emergence of drug-resistant mutations, with T790M mutations accounting for approximately 60% of all resistance. Second-generation irreversible EGFR inhibitors are effective against T790M mutations in vitro, but retain affinity for wild-type EGFR (EGFR(WT)). These inhibitors have not provided compelling clinical benefit in T790M-positive patients, apparently because of dose-limiting toxicities associated with inhibition of EGFR(WT)...
June 2014: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/24354593/emerging-protein-kinase-inhibitors-for-non-small-cell-lung-cancer
#20
REVIEW
Stephen V Liu, Deepa Subramaniam, George C Cyriac, Feras J Abdul-Khalek, Giuseppe Giaccone
INTRODUCTION: In the current paradigm of precision medicine in non-small cell lung cancer (NSCLC), the therapeutic strategy is determined by the molecular characteristics. The best examples of this approach are the kinase inhibitors that selectively target tumors bearing an epidermal growth factor receptor (EGFR) mutation or an anaplastic lymphoma kinase (ALK) rearrangement. Emerging protein kinase inhibitors may enhance our ability to effectively treat these and other genomic subtypes of NSCLC...
March 2014: Expert Opinion on Emerging Drugs
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