Non-small cell lung cancer cells acquire resistance to the ALK inhibitor alectinib by activating alternative receptor tyrosine kinases

Hideko Isozaki, Eiki Ichihara, Nagio Takigawa, Kadoaki Oohashi, Nobuaki Ochi, Masayuki Yasugi, Takashi Ninomiya, Hiromichi Yamane, Katsuyuki Hotta, Katsuya Sakai, Kunio Matsumoto, Shinobu Hosokawa, Akihiro Bessho, Toshiaki Sendo, Mitsune Tanimoto, Katsuyuki Kiura

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Abstract

Crizotinib is the standard of care for advanced non-small cell lung cancer (NSCLC) patients harboring the anaplastic lymphoma kinase (ALK) fusion gene, but resistance invariably develops. Unlike crizotinib, alectinib is a selective ALK tyrosine kinase inhibitor (TKI) with more potent antitumor effects and a favorable toxicity profile, even in crizotinib-resistant cases. However, acquired resistance to alectinib, as for other TKIs, remains a limitation of its efficacy. Therefore, we investigated the mechanisms by which human NSCLC cells acquire resistance to alectinib. We established two alectinib-resistant cell lines that did not harbor the secondary ALK mutations frequently occurring in crizotinib-resistant cells. One cell line lost the EML4-ALK fusion gene, but exhibited increased activation of insulin-like growth factor-1 receptor (IGF1R) and human epidermal growth factor receptor 3 (HER3), and overexpressed the HER3 ligand neuregulin 1. Accordingly, pharmacologic inhibition of IGF1R and HER3 signaling overcame resistance to alectinib in this cell line. The second alectinibresistant cell line displayed stimulated HGF autocrine signaling that promoted MET activation and remained sensitive to crizotinib treatment. Taken together, our findings reveal two novel mechanisms underlying alectinib resistance that are caused by the activation of alternative tyrosine kinase receptors rather than by secondary ALK mutations. These studies may guide the development of comprehensive treatment strategies that take into consideration the various approaches ALK-positive lung tumors use to withstand therapeutic insult.

Original languageEnglish
Pages (from-to)1506-1516
Number of pages11
JournalCancer Research
Volume76
Issue number6
DOIs
Publication statusPublished - Mar 15 2016

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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