Dabrafenib in advanced melanoma with BRAF V600E mutation.

Dabrafenib was recently approved by the US Food and Drug Administration for treatment of unresectable or metastatic melanoma with BRAF V600E mutations as detected by an FDA-approved test. The THxID BRAF assay, for detection of BRAF V600E mutations was concurrently approved. Dabrafenib is not indicated for the treatment of patients with wild-type BRAF melanoma, because of the potential risk of tumor promotion. About 50% of melanomas have an activating mutation in the BRAF gene, with about 80%-90% of those having a V600E mutation, and 10%-20% having a V600K mutation. Dabrafenib is a reversible, ATP-competitive inhibitor that selectively inhibits BRAF V600E kinase; preclinical data indicate that dabrafenib inhibits the MAPK pathway in BRAF V600E-mutated melanoma cells, leading to decreased proliferation and regression in xenograft models. Dabrafenib also inhibits other mutated forms of BRAF kinases, including BRAF V600K and BRAF V600D enzymes and, at higher concentrations, wild-type BRAF and CRAF kinases and other kinases (eg, SIK1, NEK11, and LIMK1). However, in vitro experiments have shown paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells exposed to BRAF inhibitors.