The pan-HER family tyrosine kinase inhibitor afatinib overcomes HER3 ligand heregulin-mediated resistance to EGFR inhibitors in non-small cell lung cancer

Kimio Yonesaka, Keita Kudo, Satomi Nishida, Takayuki Takahama, Tsutomu Iwasa, Takeshi Yoshida, Kaoru Tanaka, Masayuki Takeda, Hiroyasu Kaneda, Isamu Okamoto, Kazuto Nishio, Kazuhiko Nakagawa

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Afatinib is a second generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) characterized as an irreversible pan-human EGFR (HER) family inhibitor. Afatinib remains effective for a subpopulation of patients with non-small cell lung cancer (NSCLC) with acquired resistance to first generation EGFF-TKIs such as erlotinib. Heregulin activates HER3 in an autocrine fashion and causes erlotinib resistance in NSCLC. Here we examine whether afatinib is effective against heregulinoverexpressing NSCLCs harboring EGFR activating mutations. Afatinib but not erlotinib decreased EGFR mutant NSCLC PC9HRG cell proliferation in vitro and in mouse xenografts. Afatinib inhibited phosphorylation of the cell signaling pathway proteins HER3, EGFR, HER2, and HER4, likely by prevention of trans-phosphorylation as HER3 kinase activity is inadequate for auto-phosphorylation. Afatinib, unlike erlotinib, inhibited AKT activation, resulting in elevated apoptosis in PC9HRG cells. Clinically, a subpopulation of 33 patients with EGFR mutations and NSCLC who had received first generation EGFR-TKIs exhibited elevated plasma heregulin levels compared to healthy volunteers; one of these achieved a response with afatinib therapy despite having previously developed erlotinib resistance. Afatinib can overcome heregulinmediated resistance to erlotinib in EGFR mutant NSCLC. Further studies are necessary to determine whether heregulin can predict afatinib efficacy after development offirst generation EGFR-TKI resistance.

Original languageEnglish
Pages (from-to)33602-33611
Number of pages10
JournalOncotarget
Volume6
Issue number32
DOIs
Publication statusPublished - Jan 1 2015

All Science Journal Classification (ASJC) codes

  • Oncology

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    Yonesaka, K., Kudo, K., Nishida, S., Takahama, T., Iwasa, T., Yoshida, T., Tanaka, K., Takeda, M., Kaneda, H., Okamoto, I., Nishio, K., & Nakagawa, K. (2015). The pan-HER family tyrosine kinase inhibitor afatinib overcomes HER3 ligand heregulin-mediated resistance to EGFR inhibitors in non-small cell lung cancer. Oncotarget, 6(32), 33602-33611. https://doi.org/10.18632/oncotarget.5286