Molecular predictors of sensitivity to the MET inhibitor PHA665752 in lung carcinoma cells.

摘要

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.