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

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Item Type:	Article
Title:	Heterogeneous mechanisms of primary and acquired resistance to third-generation EGFR inhibitors
Creators Name:	Ortiz-Cuaran, S., Scheffler, M., Plenker, D., Dahmen, L., Scheel, A.H., Fernandez-Cuesta, L., Meder, L., Lovly, C.M., Persigehl, T., Merkelbach-Bruse, S., Bos, M., Michels, S., Fischer, R., Albus, K., König, K., Schildhaus, H.U., Fassunke, Jana, Ihle, M.A., Pasternack, H., Heydt, C., Becker, C., Altmüller, J., Ji, H., Müller, C., Florin, A., Heuckmann, J.M., Nuernberg, P., Ansén, S., Heukamp, L.C., Berg, J., Pao, W., Peifer, M., Buettner, R., Wolf, J., 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

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