Epithelial-to-mesenchymal transition is a mechanism of ALK inhibitor resistance in lung cancer independent of ALK mutation status

Koji Fukuda, Shinji Takeuchi, Sachiko Arai, Ryohei Katayama, Shigeki Nanjo, Azusa Tanimoto, Akihiro Nishiyama, Takayuki Nakagawa, Hirokazu Taniguchi, Takeshi Suzuki, Tadaaki Yamada, Hiroshi Nishihara, Hironori Ninomiya, Yuichi Ishikawa, Satoko Baba, Kengo Takeuchi, Atsushi Horiike, Noriko Yanagitani, Makoto Nishio, Seiji Yano

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Abstract

Mutations in the ALK gene are detectable in approximately 40% of ALK-rearranged lung cancers resistant to ALK inhibitors. Although epithelial-to-mesenchymal transition (EMT) is a mechanism of resistance to various targeted drugs, its involvement in ALK inhibitor resistance is largely unknown. In this study, we report that both ALK-mutant L1196M and EMT were concomitantly detected in a single crizotinib-resistant lesion in a patient with ALK-rearranged lung cancer. Digital PCR analyses combined with microdissection after IHC staining for EMT markers revealed that ALK L1196M was predominantly detected in epithelial-type tumor cells, indicating that mesenchymal phenotype and ALK mutation can coexist as independent mechanisms underlying ALK inhibitor-resistant cancers. Preclinical experiments with crizotinib-resistant lung cancer cells showed that EMT associated with decreased expression of miR-200c and increased expression of ZEB1 caused cross-resistance to new-generation ALK inhibitors alectinib, ceritinib, and lorlatinib. Pretreatment with the histone deacetylase (HDAC) inhibitor quisinostat overcame this resistance by reverting EMT in vitro and in vivo. These findings indicate that HDAC inhibitor pretreatment followed by a new ALK inhibitor may be useful to circumvent resistance constituted by coexistence of resistance mutations and EMT in the heterogeneous tumor. Significance: These findings show that dual inhibition of HDAC and ALK receptor tyrosine kinase activities provides a means to circumvent crizotinib resistance in lung cancer.

Original languageEnglish
Pages (from-to)1658-1670
Number of pages13
JournalCancer Research
Volume79
Issue number7
DOIs
Publication statusPublished - 2019 Apr 1

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Fukuda, K., Takeuchi, S., Arai, S., Katayama, R., Nanjo, S., Tanimoto, A., Nishiyama, A., Nakagawa, T., Taniguchi, H., Suzuki, T., Yamada, T., Nishihara, H., Ninomiya, H., Ishikawa, Y., Baba, S., Takeuchi, K., Horiike, A., Yanagitani, N., Nishio, M., & Yano, S. (2019). Epithelial-to-mesenchymal transition is a mechanism of ALK inhibitor resistance in lung cancer independent of ALK mutation status. Cancer Research, 79(7), 1658-1670. https://doi.org/10.1158/0008-5472.CAN-18-2052