HER2 Amplification: A Potential Mechanism of Acquired Resistance to EGFR Inhibition in EGFR-Mutant Lung Cancers That Lack the Second-Site EGFRT790M Mutation

被引：589

作者：

Takezawa, Ken ^{[1
]}

Pirazzoli, Valentina ^{[2
,3
]}

Arcila, Maria E. ^{[5
]}

Nebhan, Caroline A. ^{[1
]}

Song, Xiaoling ^{[2
,3
]}

de Stanchina, Elisa ^{[4
]}

Ohashi, Kadoaki ^{[1
]}

Janjigian, Yelena Y. ^{[5
]}

Spitzler, Paula J. ^{[1
]}

Melnick, Mary Ann ^{[2
,3
]}

Riely, Greg J. ^{[5
]}

Kris, Mark G. ^{[5
]}

Miller, Vincent A. ^{[5
]}

Ladanyi, Marc ^{[6
]}

Politi, Katerina ^{[2
,3
]}

Pao, William ^{[1
]}

机构：

[1] Vanderbilt Ingram Canc Ctr, Dept Med, Div Hematol Oncol, Nashville, TN 37232 USA

[2] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA

[3] Yale Univ, Sch Med, Yale Canc Ctr, New Haven, CT USA

[4] Mem Sloan Kettering Canc Ctr, Antitumor Assessment Core, Mol Pharmacol & Chem Program, New York, NY 10021 USA

[5] Mem Sloan Kettering Canc Ctr, Dept Med, Thorac Oncol Serv, Div Solid Tumor Oncol, New York, NY 10021 USA

[6] Mem Sloan Kettering Canc Ctr, Dept Pathol, Mol Diagnost Serv, New York, NY 10021 USA

来源：

CANCER DISCOVERY | 2012年 / 2卷 / 10期

关键词：

TYROSINE KINASE; COPY-NUMBER; GEFITINIB; ERLOTINIB; CHEMOTHERAPY; APOPTOSIS; THERAPY; TUMORS; BIM;

D O I：

10.1158/2159-8290.CD-12-0108

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

EGF receptor (EGFR)-mutant lung cancers eventually become resistant to treatment with EGFR tyrosine kinase inhibitors (TKI). The combination of EGFR-TKI afatinib and anti-EGFR antibody cetuximab can overcome acquired resistance in mouse models and human patients. Because afatinib is also a potent HER2 inhibitor, we investigated the role of HER2 in EGFR-mutant tumor cells. We show in vitro and in vivo that afatinib plus cetuximab significantly inhibits HER2 phosphorylation. HER2 overexpression or knockdown confers resistance or sensitivity, respectively, in all studied cell line models. FISH analysis revealed that HER2 was amplified in 12% of tumors with acquired resistance versus only 1% of untreated lung adenocarcinomas. Notably, HER2 amplification and EGFR(T790M) were mutually exclusive. Collectively, these results reveal a previously unrecognized mechanism of resistance to EGFR-TKIs and provide a rationale to assess the status and possibly target HER2 in EGFR-mutant tumors with acquired resistance to EGFR-TKIs.

引用

页码：922 / 933

页数：12

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