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

  • Authors:
    • 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
  • View Affiliations / Copyright

    Affiliations: Department of Genome Biology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan, Department of Thoracic Surgery, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan
    Copyright: © Chiba et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 2236-2244
    |
    Published online on: October 17, 2016
       https://doi.org/10.3892/ijo.2016.3736
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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 EGFR-mutated 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.
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Copy and paste a formatted citation
Spandidos Publications style
Chiba M, Togashi Y, Tomida S, Mizuuchi H, Nakamura Y, Banno E, Hayashi H, Terashima M, De Velasco MA, Sakai K, Sakai K, et al: MEK inhibitors against MET-amplified non-small cell lung cancer. Int J Oncol 49: 2236-2244, 2016.
APA
Chiba, M., Togashi, Y., Tomida, S., Mizuuchi, H., Nakamura, Y., Banno, E. ... Nishio, K. (2016). MEK inhibitors against MET-amplified non-small cell lung cancer. International Journal of Oncology, 49, 2236-2244. https://doi.org/10.3892/ijo.2016.3736
MLA
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."MEK inhibitors against MET-amplified non-small cell lung cancer". International Journal of Oncology 49.6 (2016): 2236-2244.
Chicago
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."MEK inhibitors against MET-amplified non-small cell lung cancer". International Journal of Oncology 49, no. 6 (2016): 2236-2244. https://doi.org/10.3892/ijo.2016.3736
Copy and paste a formatted citation
x
Spandidos Publications style
Chiba M, Togashi Y, Tomida S, Mizuuchi H, Nakamura Y, Banno E, Hayashi H, Terashima M, De Velasco MA, Sakai K, Sakai K, et al: MEK inhibitors against MET-amplified non-small cell lung cancer. Int J Oncol 49: 2236-2244, 2016.
APA
Chiba, M., Togashi, Y., Tomida, S., Mizuuchi, H., Nakamura, Y., Banno, E. ... Nishio, K. (2016). MEK inhibitors against MET-amplified non-small cell lung cancer. International Journal of Oncology, 49, 2236-2244. https://doi.org/10.3892/ijo.2016.3736
MLA
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."MEK inhibitors against MET-amplified non-small cell lung cancer". International Journal of Oncology 49.6 (2016): 2236-2244.
Chicago
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."MEK inhibitors against MET-amplified non-small cell lung cancer". International Journal of Oncology 49, no. 6 (2016): 2236-2244. https://doi.org/10.3892/ijo.2016.3736
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