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MEK inhibitors against MET-amplified non-small cell lung cancer.
- Source :
-
International journal of oncology [Int J Oncol] 2016 Dec; Vol. 49 (6), pp. 2236-2244. Date of Electronic Publication: 2016 Oct 17. - Publication Year :
- 2016
-
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.
- Subjects :
- A549 Cells
Carcinoma, Non-Small-Cell Lung genetics
Cell Line, Tumor
Crizotinib
Diphenylamine pharmacology
ErbB Receptors genetics
Humans
Lung Neoplasms genetics
Phosphoinositide-3 Kinase Inhibitors
Proto-Oncogene Proteins c-met genetics
Pyrazoles pharmacology
Pyridines pharmacology
Antineoplastic Agents pharmacology
Benzamides pharmacology
Carcinoma, Non-Small-Cell Lung pathology
Diphenylamine analogs & derivatives
Lung Neoplasms pathology
MAP Kinase Kinase 1 antagonists & inhibitors
Protein Kinase Inhibitors pharmacology
Proto-Oncogene Proteins c-met antagonists & inhibitors
Pyridones pharmacology
Pyrimidinones pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1791-2423
- Volume :
- 49
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- International journal of oncology
- Publication Type :
- Academic Journal
- Accession number :
- 27748834
- Full Text :
- https://doi.org/10.3892/ijo.2016.3736