The mitogen-activated protein kinase (MAPK) pathway is particularly important 
for the survival and proliferation of melanoma cells. Somatic mutations in BRAF 
and NRAS are frequently observed in melanoma. Recently, the BRAF inhibitors 
vemurafenib and dabrafenib have emerged as promising agents for the treatment of 
melanoma patients with BRAF-activating mutations. However, as BRAF inhibitors 
induce RAF paradoxical activation via RAF dimerization in BRAF wild-type cells, 
rapid emergence of acquired resistance and secondary skin tumors as well as 
presence of few effective treatment options for melanoma bearing wild-type BRAF 
(including NRAS-mutant melanoma) are clinical concerns. Here, we demonstrate 
that the selective pan-RAF inhibitor TAK-632 suppresses RAF activity in BRAF 
wild-type cells with minimal RAF paradoxical activation. Our analysis using RNAi 
and TAK-632 in preclinical models reveals that the MAPK pathway of NRAS-mutated 
melanoma cells is highly dependent on RAF. We also show that TAK-632 induces RAF 
dimerization but inhibits the kinase activity of the RAF dimer, probably because 
of its slow dissociation from RAF. As a result, TAK-632 demonstrates potent 
antiproliferative effects both on NRAS-mutated melanoma cells and BRAF-mutated 
melanoma cells with acquired resistance to BRAF inhibitors through NRAS mutation 
or BRAF truncation. Furthermore, we demonstrate that the combination of TAK-632 
and the MAPK kinase (MEK) inhibitor TAK-733 exhibits synergistic 
antiproliferative effects on these cells. Our findings characterize the unique 
features of TAK-632 as a pan-RAF inhibitor and provide rationale for its further 
investigation in NRAS-mutated melanoma and a subset of BRAF-mutated melanomas 
refractory to BRAF inhibitors.