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MEK inhibitors against MET-amplified non-small cell lung cancer
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...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
D.A. Spandidos
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5118002/ https://www.ncbi.nlm.nih.gov/pubmed/27748834 http://dx.doi.org/10.3892/ijo.2016.3736 |
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author | Chiba, Masato Togashi, Yosuke Tomida, Shuta Mizuuchi, Hiroshi Nakamura, Yu Banno, Eri Hayashi, Hidetoshi Terashima, Masato De Velasco, Marco A. Sakai, Kazuko Fujita, Yoshihiko Mitsudomi, Tetsuya Nishio, Kazuto |
author_facet | Chiba, Masato Togashi, Yosuke Tomida, Shuta Mizuuchi, Hiroshi Nakamura, Yu Banno, Eri Hayashi, Hidetoshi Terashima, Masato De Velasco, Marco A. Sakai, Kazuko Fujita, Yoshihiko Mitsudomi, Tetsuya Nishio, Kazuto |
author_sort | Chiba, Masato |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5118002 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | D.A. Spandidos |
record_format | MEDLINE/PubMed |
spelling | pubmed-51180022016-11-28 MEK inhibitors against MET-amplified non-small cell lung cancer Chiba, Masato Togashi, Yosuke Tomida, Shuta Mizuuchi, Hiroshi Nakamura, Yu Banno, Eri Hayashi, Hidetoshi Terashima, Masato De Velasco, Marco A. Sakai, Kazuko Fujita, Yoshihiko Mitsudomi, Tetsuya Nishio, Kazuto Int J Oncol Articles 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. D.A. Spandidos 2016-10-17 /pmc/articles/PMC5118002/ /pubmed/27748834 http://dx.doi.org/10.3892/ijo.2016.3736 Text en Copyright: © Chiba et al. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. |
spellingShingle | Articles Chiba, Masato Togashi, Yosuke Tomida, Shuta Mizuuchi, Hiroshi Nakamura, Yu Banno, Eri Hayashi, Hidetoshi Terashima, Masato De Velasco, Marco A. Sakai, Kazuko Fujita, Yoshihiko Mitsudomi, Tetsuya Nishio, Kazuto MEK inhibitors against MET-amplified non-small cell lung cancer |
title | MEK inhibitors against MET-amplified non-small cell lung cancer |
title_full | MEK inhibitors against MET-amplified non-small cell lung cancer |
title_fullStr | MEK inhibitors against MET-amplified non-small cell lung cancer |
title_full_unstemmed | MEK inhibitors against MET-amplified non-small cell lung cancer |
title_short | MEK inhibitors against MET-amplified non-small cell lung cancer |
title_sort | mek inhibitors against met-amplified non-small cell lung cancer |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5118002/ https://www.ncbi.nlm.nih.gov/pubmed/27748834 http://dx.doi.org/10.3892/ijo.2016.3736 |
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