Many RAS pathway inhibitors, including pan-RAF inhibitors, have shown significant anti-
tumor activities in both solid and hematological
tumors. The pan-RAF inhibitor,
TAK-580, is a representative of the novel RAF inhibitors that act by disrupting RAF homo- or heterodimerization. In this study, we examined the anti-
tumor effects of
TAK-580 used as monotherapy or in combination with
bortezomib,
lenalidomide, or other novel agents in
multiple myeloma (MM) cells in vitro.
TAK-580 monotherapy potently targeted
proteins in the RAS-RAF-
MEK-ERK signaling pathway and induced potent cytotoxicity and apoptosis in MM cell lines and myeloma cells from patients with newly diagnosed and relapsed and/or refractory MM, compared with a representative RAF inhibitor,
dabrafenib. Normal donor peripheral blood B lymphocytes and cord blood CD34-positive cells were not affected. Importantly,
TAK-580 significantly inhibited phospho-FOXO3 and induced upregulation of BimL and BimS in a dose-dependent manner, finally leading to apoptosis in MM cells. Moreover,
TAK-580 enhanced
bortezomib-induced cytotoxicity and apoptosis in MM cells via the FOXO3-Bim axis and the terminal unfolded protein response. Importantly,
TAK-580 also enhanced
lenalidomide-induced cytotoxicity and apoptosis in MM cells. Taken together, our results provide the rationale for
TAK-580 monotherapy and/or treatment in combination with novel agents to improve outcomes in patients with MM.