Heterogeneous Mechanisms of Primary and Acquired Resistance to Third-Generation EGFR Inhibitors

被引：241

作者：

Ortiz-Cuaran, Sandra ^{[1
]}

Scheffler, Matthias ^{[2
,3
]}

Plenker, Dennis ^{[1
,4
]}

Dahmen, Ilona ^{[1
]}

Scheel, Andreas H. ^{[5
]}

Fernandez-Cuesta, Lynnette ^{[1
,6
]}

Meder, Lydia ^{[5
]}

Lovly, Christine M. ^{[7
]}

Persigehl, Thorsten ^{[8
]}

Merkelbach-Bruse, Sabine ^{[5
]}

Bos, Marc ^{[1
]}

Michels, Sebastian ^{[2
,3
]}

Fischer, Rieke ^{[2
,3
]}

Albus, Kerstin ^{[5
]}

Koenig, Katharina ^{[9
]}

Schildhaus, Hans-Ulrich ^{[10
]}

Fassunke, Jana ^{[5
]}

Ihle, Michaela A. ^{[5
]}

PasternackO, Helen ^{[5
,11
,12
,13
,14
]}

Heydt, Carina ^{[5
]}

Becker, Christian ^{[15
]}

Altmueller, Janine ^{[15
]}

Ji, Hongbin ^{[16
,17
]}

Mueller, Christian ^{[1
]}

Florin, Alexandra ^{[5
]}

Heuckmann, Johannes M. ^{[18
]}

Nuernberg, Peter ^{[15
]}

Ansen, Sascha ^{[2
,3
]}

Heukamp, Lukas C. ^{[5
,18
]}

Berg, Johannes ^{[19
]}

Pao, William ^{[7
]}

Peifer, Martin ^{[1
,20
]}

Buettner, Reinhard ^{[5
]}

Wolfe, Juergen ^{[2
,3
]}

Thomas, Roman K. ^{[1
,5
]}

Sos, Martin L. ^{[4
]}

机构：

[1] Univ Cologne, Fac Med, Ctr Integrated Oncol Cologne Bonn, Dept Translat Genom, Cologne, Germany

[2] Univ Hosp Cologne, Ctr Integrated Oncol Cologne Bonn, Lung Canc Grp Cologne, Dept Internal Med 1, Cologne, Germany

[3] Univ Hosp Cologne, Ctr Integrated Oncol Cologne Bonn, Network Genom Med Lung Canc, Cologne, Germany

[4] Univ Hosp Cologne, Ctr Integrated Oncol, Mol Pathol, Cologne, Germany

[5] Univ Hosp Cologne, Inst Pathol, Ctr Integrated Oncol, Cologne, Germany

[6] Int Agcy Res Canc IARC WHO, Genet Sect, Genet Canc Susceptibil Grp, Lyon, France

[7] Vanderbilt Univ, Dept Med, Nashville, TN USA

[8] Univ Hosp Cologne, Dept Radiol, Cologne, Germany

[9] Labor Dr Quade & Kollegen GmbH, Cologne, Germany

[10] Univ Hosp Gottingen, Inst Pathol, Gottingen, Germany

[11] Univ Hosp Luebeck, Pathol, Lubeck, Germany

[12] Leibniz Res Ctr Borstel, Lubeck, Germany

[13] Univ Hosp Luebeck, Pathol, Borstel, Germany

[14] Leibniz Res Ctr Borstel, Borstel, Germany

[15] Univ Cologne, CCG, Cologne, Germany

[16] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol,CAS Ctr Excellence Mol C, Innovat Ctr Cell Signaling Network,Key Lab Syst B, Shanghai, Peoples R China

[17] Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China

[18] NEO New Oncol AG, Cologne, Germany

[19] Univ Cologne, Inst Theoret Phys, Cologne, Germany

[20] Univ Cologne, CMMC, Cologne, Germany

来源：

CLINICAL CANCER RESEARCH | 2016年 / 22卷 / 19期

基金：

美国国家卫生研究院;

关键词：

GROWTH-FACTOR RECEPTOR; CELL LUNG-CANCER; KINASE INHIBITORS; MET AMPLIFICATION; CONFERS RESISTANCE; KRAS MUTATION; AZD9291; MUTANT; GEFITINIB; ERLOTINIB;

D O I：

10.1158/1078-0432.CCR-15-1915

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：4837 / 4847

页数：11

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