Identification of MET and SRC activation in melanoma cell lines showing primary resistance to PLX4032.

摘要: PLX4032/vemurafenib is a first-in-class small-molecule BRAFV600E inhibitor with clinical activity in patients BRAF mutant melanoma. Nevertheless, drug resistance develops treated patients, and strategies to overcome primary acquired are required. To explore the molecular mechanisms involved PLX4032, we investigated its effects on cell proliferation signaling panel of 27 genetically characterized patient-derived melanoma lines. Cell sensitivity PLX4032 was dependent independent from other gene alterations that commonly occur such as PTEN loss, BRAF, MITF amplification. Two lines lacking harboring different set genetic were studied models resistance. Treatment MEK UO126 but not inhibited growth ERK activation. Resistance maintained after CRAF down-regulation by siRNA indicating alternative activation MEK-ERK signaling. Genetic characterization multiplex ligation-dependent probe amplification analysis phosphotyrosine MALDI-TOF mass spectrometry revealed MET SRC signaling, associated CTNNB1 CCND1 genes, respectively. The combination drugs or targeting effective inhibiting reducing invasion migration cells amplification; similar observed line, role for PLX4032. Our results support development classification subtypes more therapies.