HER2 amplification: A potential mechanism of acquired resistance to egfr inhibition in EGFR -mutant lung cancers that lack the second-site EGFR T790M mutation

Ken Takezawa, Valentina Pirazzoli, Maria E. Arcila, Caroline A. Nebhan, Xiaoling Song, Elisa de Stanchina, Kadoaki Ohashi, Yelena Y. Janjigian, Paula J. Spitzler, Mary Ann Melnick, Greg J. Riely, Mark G. Kris, Vincent A. Miller, Marc Ladanyi, Katerina Politi, William Pao

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Abstract

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 signifi cantly inhibits HER2 phosphorylation. HER2 overexpression or knockdown confers resistance or sensitivity, respectively, in all studied cell line models. FISH analysis revealed that HER2 was amplifi ed in 12% of tumors with acquired resistance versus only 1% of untreated lung adenocarcinomas. Notably, HER2 amplifi cation 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. SIGNIFICANCE: Because all EGFR -mutant lung adenocarcinomas eventually develop resistance to TKI therapy, understanding mechanisms of acquired resistance may improve clinical outcomes. These results implicate HER2 as a novel protein involved in the sensitivity or resistance of EGFR -mutant lung cancer and provide a rationale to assess the status of and possibly target HER2 in such tumors.

Original languageEnglish
Pages (from-to)922-933
Number of pages12
JournalCancer discovery
Volume2
Issue number10
DOIs
Publication statusPublished - Oct 1 2012
Externally publishedYes

ASJC Scopus subject areas

  • Oncology

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    Takezawa, K., Pirazzoli, V., Arcila, M. E., Nebhan, C. A., Song, X., de Stanchina, E., Ohashi, K., Janjigian, Y. Y., Spitzler, P. J., Melnick, M. A., Riely, G. J., Kris, M. G., Miller, V. A., Ladanyi, M., Politi, K., & Pao, W. (2012). HER2 amplification: A potential mechanism of acquired resistance to egfr inhibition in EGFR -mutant lung cancers that lack the second-site EGFR T790M mutation. Cancer discovery, 2(10), 922-933. https://doi.org/10.1158/2159-8290.CD-12-0108