MEK inhibitors against MET-amplified non-small cell lung cancer

Masato Chiba, Yosuke Togashi, Shuta Tomida, Hiroshi Mizuuchi, Yu Nakamura, Eri Banno, Hidetoshi Hayashi, Masato Terashima, Marco A. De Velasco, Kazuko Sakai, Yoshihiko Fujita, Tetsuya Mitsudomi, Kazuto Nishio

Research output: Contribution to journalReview article

11 Citations (Scopus)

Abstract

Several receptor tyrosine kinases (RTKs) including EGFR, ALK, and MET have been identified as therapeutic targets in non-small cell lung cancer (NSCLC). Among the downstream pathways of RTKs, the MAPK pathway is particularly important for cancer cell proliferation, differentiation, and survival. In this study, the effects of MEK inhibitors (trametinib and PD0325901) in several NSCLC cell lines with driver gene alterations, especially RTK genes, were tested in vitro using an MTT assay, and a wide range of sensitivities was found. In particular, all the EGFR-mutated cell lines were resistant to MEK inhibitors, whereas all the MET-amplified cell lines were sensitive. A bioinformatics technique and western blot analyses showed that the PI3K/AKT pathway is more activated in EGFRmutated NSCLC than in MET-amplified NSCLC, and a PI3K inhibitor enhanced the sensitivity to trametinib in the EGFR-mutated cell lines, suggesting that this pathway is associated with resistance to MEK inhibitors. Although the HCC827 cell line (EGFR mutation) was resistant to MEK inhibitors, the HCC827CNXR cell line, whose driver gene shifts from EGFR to MET, exhibited enhanced sensitivity to MEK inhibitors, indicating the biological importance of the MAPK pathway for MET-amplified NCSLC. Furthermore, a synergistic effect of crizotinib (a MET inhibitor) and trametinib was observed in MET-amplified NCLC cell lines. Our findings indicate that the MAPK pathway is biologically important for MET-amplified NSCLC and strongly encourage the development of combination therapy with a MET inhibitor and a MEK inhibitor against MET-amplified NSCLC.

Original languageEnglish
Pages (from-to)2236-2244
Number of pages9
JournalInternational journal of oncology
Volume49
Issue number6
DOIs
Publication statusPublished - Dec 2016

Keywords

  • MAPK pathway
  • MEK inhibitor
  • MET amplification
  • MET inhibitor
  • Non-small cell lung cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Chiba, M., Togashi, Y., Tomida, S., Mizuuchi, H., Nakamura, Y., Banno, E., Hayashi, H., Terashima, M., De Velasco, M. A., Sakai, K., Fujita, Y., Mitsudomi, T., & Nishio, K. (2016). MEK inhibitors against MET-amplified non-small cell lung cancer. International journal of oncology, 49(6), 2236-2244. https://doi.org/10.3892/ijo.2016.3736