TY - JOUR
T1 - Heterogeneous mechanisms of primary and acquired resistance to third-generation EGFR inhibitors
AU - Ortiz-Cuaran, Sandra
AU - Scheffler, Matthias
AU - Plenker, Dennis
AU - Dahmen, Llona
AU - Scheel, Andreas H.
AU - Fernandez-Cuesta, Lynnette
AU - Meder, Lydia
AU - Lovly, Christine M.
AU - Persigehl, Thorsten
AU - Merkelbach-Bruse, Sabine
AU - Bos, Marc
AU - Michels, Sebastian
AU - Fischer, Rieke
AU - Albus, Kerstin
AU - König, Katharina
AU - Schildhaus, Hans Ulrich
AU - Fassunke, Jana
AU - Ihle, Michaela A.
AU - Pasternack, Helen
AU - Heydt, Carina
AU - Becker, Christian
AU - Altmüller, Janine
AU - Ji, Hongbin
AU - Müller, Christian
AU - Florin, Alexandra
AU - Heuckmann, Johannes M.
AU - Nuernberg, Peter
AU - Ans, Sascha
AU - Heukamp, Lukas C.
AU - Berg, Johannes
AU - Pao, William
AU - Peifer, Martin
AU - Buettner, Reinhard
AU - Wolf, Jürgen
AU - Thomas, Roman K.
AU - Sos, Martin L.
N1 - Funding Information:
This work was supported by the German federal state North Rhine Westphalia (NRW) and by the European Union (European Regional Development Fund: Investing in Your Future) as part of the PerMed. NRW initiative (grant 005-1111-0025; to R.K. Thomas, J. Wolf, and R. Buettner) and by the German Ministry of Science and Education (BMBF) as part of the e:Med program (grant no. 01ZX1303; to R.K. Thomas, J. Wolf, R. Buettner, andM. Peifer and grant no. 01ZX1406; to M.L. Sos and M. Peifer). Additional funding was provided by the German Cancer Aid (Deutsche Krebshilfe) as part of the small-cell lung cancer genome sequencing consortium (grant ID: 109679; to R.K. Thomas, M. Peifer, and R. Buettner), by SFB832 (TP6; to R.K. Thomas), by the Deutsche Forschungsgemeinschaft (DFG; through TH1386/3-1; to R.K. Thomas and M.L. Sos), by the Deutsche Krebshilfe as part of the Oncology Centers of Excellence funding program (to R. Buettner, R.K. Thomas, and J. Wolf) by the EUFramework program CURELUNG (HEALTH-F2-2010-258677; to R.K. Thomas and J. Wolf), by a Stand Up to Cancer Innovative Research Grant (SU2C-AACRIR60109; to R.K. Thomas) Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research; and by the German Consortium for Translational Cancer Research (DKTK) Joint Funding program. This study was supported in part by the National Institutes of Health (NIH) and National Cancer Institute (NCI) R01CA121210 (to C.M. Lovly) and P01CA129243 (to C.M. Lovly). C.M. Lovly was additionally supported by a Damon Runyon Clinical Investigator Award a LUNGevity Career Development Award, a V Foundation Scholar in Training Award, and an AACR-Genentech Career Development Award.
Publisher Copyright:
© 2016 American Association for Cancer Research.
Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2016/10/1
Y1 - 2016/10/1
N2 - Purpose: To identify novel mechanisms of resistance to thirdgeneration 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 KRASG12S 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. Clin Cancer Res; 22(19); 4837-47.
AB - Purpose: To identify novel mechanisms of resistance to thirdgeneration 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 KRASG12S 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. Clin Cancer Res; 22(19); 4837-47.
UR - http://www.scopus.com/inward/record.url?scp=84991241383&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-15-1915
DO - 10.1158/1078-0432.CCR-15-1915
M3 - Journal articles
C2 - 27252416
AN - SCOPUS:84991241383
SN - 1078-0432
VL - 22
SP - 4837
EP - 4847
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 19
ER -
