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Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
Published on: August 11, 2017
Molecular predictors of sensitivity to the MET inhibitor PHA665752 in lung carcinoma cells
Daisuke Matsubara1, Shumpei Ishikawa, Sachiko Oguni
1Department of Pathology, Jichi Medical University, Yakushiji, Shimotsuke, Tochigi, Japan.
Background:
No comprehensive data are available on the molecular predictors of sensitivity to MET inhibitor in lung carcinomas.
Methods:
We examined the efficacy of the MET inhibitor PHA665752 in 41 cell lines of non-small lung carcinoma to determine whether sensitivity to the MET inhibitor is correlated with the (1) genetic statuses of MET, epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2, and KRAS, (2) MET phosphorylation and its downstream signaling pathways, or (3) epithelial-mesenchymal transition.
Results:
Of the 41 cells, 8 were highly or intermediately sensitive to PHA665752, and the remainder were PHA665752 resistant. The sensitive cells (n = 8) included not only 4 of 4 MET-amplified cell lines but also 2 of 11 KRAS-mutated cell lines and 1 of 6 EGFR-mutated cell lines. Unlike the MET-amplified cell lines, both the MET-mutated cell lines were PHA665752 resistant. High phospho-MET was not restricted to the four MET-amplified cell lines. To the contrary, it was also found in 9 of 37 MET-nonamplified cell lines, including 3 of 6 EGFR-mutated cell lines and 4 of 11 KRAS-mutated cell lines. High phospho-MET was correlated with PHA665752 sensitivity in the entire panel of cell lines, especially in the KRAS-mutated cells. The AKT and ERK pathways in the high phospho-MET cell lines were dependent on MET activation in MET-amplified and KRAS-mutated cells but not in EGFR-mutated and human epidermal growth factor receptor 2-amplified cells.
Conclusions:
MET amplification is an excellent predictor of PHA665752 sensitivity but not the sole predictor. High phospho-MET and dependence of the AKT and ERK pathways on MET activation may predict sensitivity to PHA665752, especially in KRAS-mutated cell lines.
Insights
MET amplification predicts sensitivity to PHA665752 in lung cancer, but high phospho-MET and specific pathway activations, particularly in KRAS-mutated cells, may also indicate response to MET inhibitors.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Limited data exists on molecular predictors for MET inhibitor sensitivity in lung carcinomas.
- Understanding these predictors is crucial for targeted therapy development.
Purpose of the Study:
- To investigate molecular predictors of sensitivity to the MET inhibitor PHA665752 in non-small cell lung carcinoma.
- To correlate sensitivity with genetic status, MET phosphorylation, downstream signaling, and epithelial-mesenchymal transition.
Main Methods:
- Screening of 41 non-small cell lung carcinoma cell lines with the MET inhibitor PHA665752.
- Analysis of genetic alterations in MET, EGFR, ERBB2, and KRAS.
- Assessment of MET phosphorylation and downstream AKT/ERK pathway activation.
Main Results:
- Eight cell lines showed sensitivity to PHA665752, including MET-amplified, KRAS-mutated, and EGFR-mutated lines.
- High phospho-MET levels correlated with PHA665752 sensitivity, particularly in KRAS-mutated cells.
- MET pathway dependence varied among genetic subtypes, with MET-amplified and KRAS-mutated cells showing dependence.
Conclusions:
- MET amplification is a strong predictor, but not the only one, for PHA665752 sensitivity.
- High phospho-MET and MET-dependent AKT/ERK signaling may predict sensitivity, especially in KRAS-mutated lung carcinomas.