Abstract 2588: Anti-tumor effect of afatinib, an irreversible EGFR/HER2 dual inhibitor, in lung cancers harboring HER2 oncogene

Abstract

Abstract HER2 is a member of the EGFR family of tyrosine kinase receptors and plays important roles in the pathogenesis of certain human cancers. In non-small cell lung cancer (NSCLC), HER2 amplification or mutations are reported. However, little is known about the benefit of HER2-targeted therapy for NSCLC harboring HER2 alteration. In this study, we investigated the anti-tumor effect of afatinib, an irreversible EGFR/HER2 dual inhibitor, in lung cancers harboring HER2 oncogene alteration, including the novel HER2 mutations in transmembrane domain which we recently identified. Ectopically overexpressing HER2 wild-type or mutant (G776V,Cins, A775insYVMA, G660D, and V659E) in normal bronchial epithelial cells, BEAS2B, showed constitutive autophosphorylation of HER2 and activation of downstream signaling. They were sensitive to afatinib, but insensitive to EGFR-TKI (gefitinib). Furthermore, we examined anti-tumor activity of afatinib and gefitinib in several NSCLC cell lines, and investigated the association between their genetic alteration and sensitivity to afatinib treatment. Afatinib down-regulated the phosphorylation of HER2, EGFR, and their downstream signalings, and induced anti-proliferative effect through a G1 arrest and apoptotic cell death in HER2 altered cells (H2170, Calu-3, and H1781). Whereas, HER2 non-dependent NSCLC cells (A549, H1299, and H1993) were insensitive to afatinib. Our results strongly suggest that afatinib is a therapeutic option for NSCLC patients with HER2 alteration. Citation Format: Ken Suzawa, Shinichi Toyooka, Masakiyo Sakaguchi, Tomoaki Ohtsuka, Mototsugu Watanabe, Shinsuke Hashida, Yuho Maki, Hiromasa Yamamoto, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi. Anti-tumor effect of afatinib, an irreversible EGFR/HER2 dual inhibitor, in lung cancers harboring HER2 oncogene. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2588. doi:10.1158/1538-7445.AM2015-2588