Differential sensitivity of melanoma cell lines with differing B‐Raf mutational status to the new oncogenic B‐Raf kinase inhibitor UAI‐201

Abstract

The antiproliferative effect of the new oncogenic B‐Raf targeting drug UAI‐201 on 2 types of melanoma cell lines with differing B‐Raf mutational status was examined, and the underlying mechanisms were investigated. In cellular assays, UAI‐201 displayed high selectivity for tumor cells bearing B‐Raf(V600E), showing more than 1,000‐fold higher inhibition of their proliferation than wild‐type B‐Raf‐bearing cells. As expected, UAI‐201 completely abolished MEK‐ERK phosphorylation in A375P cells harboring B‐Raf(V600E). In SK‐MEL‐2 cells expressing B‐Raf(WT), UAI‐201 caused the paradoxical activation of the MAPK pathway but to a much lesser extent than that observed of other oncogenic B‐Raf inhibitors. These data suggest that UAI‐201 may be a more ideal B‐Raf inhibitor capable of preserving potency against oncogenic B‐Raf while minimizing the paradoxical activation of MAPK signaling. In addition, we showed that UAI‐201 treatment of A375P cells simultaneously induced cellular autophagy and apoptosis, as determined by GFP‐LC3 and caspase‐3 assays, respectively. Moreover, our results suggested that apoptosis and autophagy may cooperate in the induction of cell death in UAI‐201‐treated cells, which is dependent on Raf‐1 signaling. Collectively, our data suggest that UAI‐201 may be an effective B‐Raf inhibitor and a potential therapeutic strategy for B‐Raf( WT) and Ras mutant melanoma.