HER2 amplification: a potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFRT790M mutation.

Takezawa K, Pirazzoli V, Arcila ME, Nebhan CA, Song X, de Stanchina E, Ohashi K, Janjigian YY, Spitzler PJ, Melnick MA, Riely GJ, Kris MG, Miller VA, Ladanyi M, Politi K, Pao W
Cancer Discov. 2012 2 (10): 922-33

PMID: 22956644 · PMCID: PMC3473100 · DOI:10.1158/2159-8290.CD-12-0108

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.

MeSH Terms (26)

Adenocarcinoma Adenocarcinoma of Lung Afatinib Animals Antibodies, Monoclonal Antibodies, Monoclonal, Humanized Antineoplastic Agents Cell Line, Tumor Cetuximab Class I Phosphatidylinositol 3-Kinases Drug Resistance, Neoplasm ErbB Receptors Erlotinib Hydrochloride Humans Lung Neoplasms Mice Mice, Nude Molecular Targeted Therapy Mutation Phosphatidylinositol 3-Kinases Phosphorylation Protein Kinase Inhibitors Quinazolines Receptor, ErbB-2 RNA, Small Interfering RNA Interference

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