Therapeutic strategies for afatinib-resistant lung cancer harboring HER2 alterations

Hidejiro Torigoe, Kazuhiko Shien, Tatsuaki Takeda, Takahiro Yoshioka, Kei Namba, Hiroki Sato, Ken Suzawa, Hiromasa Yamamoto, Junichi Soh, Masakiyo Sakaguchi, Shuta Tomida, Kazunori Tsukuda, Shinichiro Miyoshi, Shinichi Toyooka

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Human epidermal growth factor receptor 2 (HER2) plays an important role in the pathogenesis of various cancers. HER2 alterations have been suggested to be a therapeutic target in non-small-cell lung cancer (NSCLC), just as in breast and gastric cancers. We previously reported that the pan-HER inhibitor afatinib could be a useful therapeutic agent as HER2-targeted therapy for patients with NSCLC harboring HER2 alterations. However, acquired resistance to afatinib was observed in the clinical setting, similar to the case for other HER inhibitors. Thus, elucidation of the mechanisms underlying the development of acquired drug resistance and exploring means to overcome acquired drug resistance are important issues in the treatment of NSCLC. In this study, we experimentally established afatinib-resistant cell lines from NSCLC cell lines harboring HER2 alterations, and investigated the mechanisms underlying the acquisition of drug resistance. The established cell lines showed several unique afatinib-resistance mechanisms, including MET amplification, loss of HER2 amplification and gene expression, epithelial-to-mesenchymal transition (EMT) and acquisition of cancer stem cell (CSC)-like features. The afatinib-resistant cell lines showing MET amplification were sensitive to the combination of afatinib plus crizotinib (a MET inhibitor), both in vitro and in vivo. The resistant cell lines which showed EMT or had acquired CSC-like features remained sensitive to docetaxel, like the parental cells. These findings may provide clues to countering the resistance to afatinib in NSCLC patients with HER2 alterations.

Original languageEnglish
Pages (from-to)1493-1502
Number of pages10
JournalCancer Science
Volume109
Issue number5
DOIs
Publication statusPublished - May 2018

Keywords

  • acquired resistance
  • afatinib
  • human epidermal growth factor receptor 2
  • lung cancer
  • non-small cell lung cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Torigoe, H., Shien, K., Takeda, T., Yoshioka, T., Namba, K., Sato, H., Suzawa, K., Yamamoto, H., Soh, J., Sakaguchi, M., Tomida, S., Tsukuda, K., Miyoshi, S., & Toyooka, S. (2018). Therapeutic strategies for afatinib-resistant lung cancer harboring HER2 alterations. Cancer Science, 109(5), 1493-1502. https://doi.org/10.1111/cas.13571