PLX4032, a selective BRAFV600E kinase inhibitor, activates the ERK pathway and enhances cell migration and proliferation of BRAFWT melanoma cells

摘要: BRAFV600E/K is a frequent mutationally active tumor-specific kinase in melanomas that currently targeted for therapy by the specific inhibitor PLX4032. Our studies with melanoma tumor cells are and BRAFWT showed that, paradoxically, while PLX4032 inhibited ERK1/2 highly sensitive BRAFV600E/K, it activated pathway resistant cells, via RAF1 activation, regardless of status mutations NRAS or PTEN. The persistently triggered downstream effectors induced changes expression wide-spectrum genes associated cell cycle control. Furthermore, increased rate proliferation growth factor-dependent Q61L mutant primary reduced adherence mobility from advanced lesions. results suggest drug can confer an advantage to metastatic vivo provide markers monitoring clinical responses.