Ortiz-Cuaran, Sandra, Scheffler, Matthias ORCID: 0000-0002-9031-1368, Plenker, Dennis, Dahmen, Ilona, Scheel, Andreas H., Fernandez-Cuesta, Lynnette ORCID: 0000-0002-0724-6703, Meder, Lydia ORCID: 0000-0002-9547-5812, Lovly, Christine M., Persigehl, Thorsten, Merkelbach-Bruse, Sabine, Bos, Marc, Michels, Sebastian, Fischer, Rieke, Albus, Kerstin, Koenig, Katharina, Schildhaus, Hans-Ulrich, Fassunke, Jana, Ihle, Michaela A., PasternackO, Helen, Heydt, Carina, Becker, Christian, Altmueller, Janine, Ji, Hongbin, Mueller, Christian, Florin, Alexandra, Heuckmann, Johannes M., Nuernberg, Peter, Ansen, Sascha, Heukamp, Lukas C., Berg, Johannes, Pao, William, Peifer, Martin ORCID: 0000-0002-5243-5503, Buettner, Reinhard, Wolfe, Juergen, Thomas, Roman K. and Sos, Martin L. (2016). Heterogeneous Mechanisms of Primary and Acquired Resistance to Third-Generation EGFR Inhibitors. Clin. Cancer Res., 22 (19). S. 4837 - 4848. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1557-3265

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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. (C) 2016 AACR.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Ortiz-Cuaran, SandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scheffler, MatthiasUNSPECIFIEDorcid.org/0000-0002-9031-1368UNSPECIFIED
Plenker, DennisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dahmen, IlonaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scheel, Andreas H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fernandez-Cuesta, LynnetteUNSPECIFIEDorcid.org/0000-0002-0724-6703UNSPECIFIED
Meder, LydiaUNSPECIFIEDorcid.org/0000-0002-9547-5812UNSPECIFIED
Lovly, Christine M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Persigehl, ThorstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Merkelbach-Bruse, SabineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bos, MarcUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Michels, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischer, RiekeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Albus, KerstinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koenig, KatharinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schildhaus, Hans-UlrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fassunke, JanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ihle, Michaela A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
PasternackO, HelenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heydt, CarinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Becker, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ji, HongbinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mueller, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Florin, AlexandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heuckmann, Johannes M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ansen, SaschaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heukamp, Lukas C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Berg, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pao, WilliamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peifer, MartinUNSPECIFIEDorcid.org/0000-0002-5243-5503UNSPECIFIED
Buettner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wolfe, JuergenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomas, Roman K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sos, Martin L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-261373
DOI: 10.1158/1078-0432.CCR-15-1915
Journal or Publication Title: Clin. Cancer Res.
Volume: 22
Number: 19
Page Range: S. 4837 - 4848
Date: 2016
Publisher: AMER ASSOC CANCER RESEARCH
Place of Publication: PHILADELPHIA
ISSN: 1557-3265
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GROWTH-FACTOR RECEPTOR; CELL LUNG-CANCER; KINASE INHIBITORS; MET AMPLIFICATION; CONFERS RESISTANCE; KRAS MUTATION; AZD9291; MUTANT; GEFITINIB; ERLOTINIBMultiple languages
OncologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/26137

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