Activated MET acts as a salvage signal after treatment with alectinib, a selective ALK inhibitor, in ALK-positive non-small cell lung cancer

Akihiro Kogita, Yosuke Togashi, Hidetoshi Hayashi, Eri Banno, Masato Terashima, Marco A. De Velasco, Kazuko Sakai, Yoshihiko Fujita, Shuta Tomida, Yoshifumi Takeyama, Kiyotaka Okuno, Kazuhiko Nakagawa, Kazuto Nishio

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Non-small cell lung cancer (NSCLC) carrying echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangements is hypersensitive to ALK inhibitors, including crizotinib and alectinib. Crizotinib was initially designed as a MET inhibitor, whereas alectinib is a selective ALK inhibitor. The MET signal, which is inhibited by crizotinib but not by alectinib, is dysregulated in many human cancers. However, the role of the MET signal in ALK-positive NSCLC remains unclear. In this study, we found that hepatocyte growth factor (HGF), ligand of MET, mediated the resistance to alectinib, but not to crizotinib, via the MET signal in ALK-positive NSCLC cell lines (H3122 and H2228 cell lines). In addition, alectinib activated the MET signal even in the absence of HGF and the inhibition of the MET signal enhanced the efficacy of alectinib. These findings suggest that activated MET acts as a salvage signal in ALK-positive NSCLC. This novel role of the MET signal in ALK-positive NSCLC may pave the way for further clinical trials examining MET inhibitors.

Original languageEnglish
Pages (from-to)1025-1030
Number of pages6
JournalInternational journal of oncology
Volume46
Issue number3
DOIs
Publication statusPublished - Mar 1 2015
Externally publishedYes

Keywords

  • Alectinib
  • Crizotinib
  • EML4-ALK rearrangement
  • MET
  • Non-small cell lung cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Activated MET acts as a salvage signal after treatment with alectinib, a selective ALK inhibitor, in ALK-positive non-small cell lung cancer'. Together they form a unique fingerprint.

  • Cite this

    Kogita, A., Togashi, Y., Hayashi, H., Banno, E., Terashima, M., De Velasco, M. A., Sakai, K., Fujita, Y., Tomida, S., Takeyama, Y., Okuno, K., Nakagawa, K., & Nishio, K. (2015). Activated MET acts as a salvage signal after treatment with alectinib, a selective ALK inhibitor, in ALK-positive non-small cell lung cancer. International journal of oncology, 46(3), 1025-1030. https://doi.org/10.3892/ijo.2014.2797