Heterogeneous mechanisms of primary and acquired resistance to third-generation EGFR inhibitors

Item Type:	Article
Title:	Heterogeneous mechanisms of primary and acquired resistance to third-generation EGFR inhibitors
Creators Name:	Ortiz-Cuaran, S. and Scheffler, M. and Plenker, D. and Dahmen, L. and Scheel, A.H. and Fernandez-Cuesta, L. and Meder, L. and Lovly, C.M. and Persigehl, T. and Merkelbach-Bruse, S. and Bos, M. and Michels, S. and Fischer, R. and Albus, K. and König, K. and Schildhaus, H.U. and Fassunke, Jana and Ihle, M.A. and Pasternack, H. and Heydt, C. and Becker, C. and Altmüller, J. and Ji, H. and Müller, C. and Florin, A. and Heuckmann, J.M. and Nuernberg, P. and Ansén, S. and Heukamp, L.C. and Berg, J. and Pao, W. and Peifer, M. and Buettner, R. and Wolf, J. and Thomas, R.K. and Sos, M.L.
Abstract:	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. RESULTS: We found recurrent amplification of either MET or ERBB2 in tumors that were resistant or developed resistance to third-generation EGFR inhibitors and show that ERBB2 and MET activation can confer resistance to these compounds. Furthermore, we identified a KRAS(G12S) mutation in a patient with acquired resistance to AZD9291 as a potential driver of acquired resistance. Finally, we show that dual inhibition of EGFR/MEK might be a viable strategy to overcome resistance in EGFR-mutant cells expressing mutant KRAS CONCLUSIONS: Our data suggest that heterogeneous mechanisms of resistance can drive primary and acquired resistance to third-generation EGFR inhibitors and provide a rationale for potential combination strategies.
Keywords:	Acrylamides, Adenocarcinoma, Adenocarcinoma of Lung, Aniline Compounds, Antineoplastic Agents, ErbB Receptors, Lung Neoplasms, Neoplasm Drug Resistance, Pyrimidines
Source:	Clinical Cancer Research
ISSN:	1078-0432
Publisher:	American Association for Cancer Research
Volume:	22
Number:	19
Page Range:	4837-4847
Date:	2 October 2016
Official Publication:	https://doi.org/10.1158/1078-0432.CCR-15-1915
PubMed:	View item in PubMed

Repository Staff Only: item control page