Anti-tumor activities of the new oral pan-RAF inhibitor, TAK-580, used as monotherapy or in combination with novel agents in multiple myeloma
Rikio Suzuki 1, Yuka Kitamura 2, Yoshihiko Nakamura 2, Hibiki Akashi 1, Yoshiaki Ogawa 1, Hiroshi Kawada 1, Kiyoshi Ando 1 2

Many RAS path inhibitors, including pan-RAF inhibitors, have proven significant anti-tumor activities both in solid and hematological tumors. The pan-RAF inhibitor, TAK-580, is really a associated with the novel RAF inhibitors that act by disrupting RAF homo- or heterodimerization. Within this study, we examined the anti-tumor results of TAK-580 utilized as monotherapy or in conjunction with bortezomib, lenalidomide, or any other novel agents in multiple myeloma (MM) cells in vitro. TAK-580 monotherapy potently targeted proteins within the RAS-RAF-MEK-ERK signaling path and caused potent cytotoxicity and apoptosis in MM cell lines and myeloma cells from patients with recently diagnosed and relapsed and/or refractory MM, in contrast to an agent RAF inhibitor, dabrafenib. Normal donor peripheral bloodstream B lymphocytes and twine bloodstream CD34-positive cells weren’t affected. Importantly, TAK-580 considerably inhibited phospho-FOXO3 and caused upregulation of BimL and BimS inside a dose-dependent manner, finally resulting in apoptosis in MM cells. Furthermore, TAK-580 enhanced bortezomib-caused cytotoxicity and apoptosis in MM cells through the FOXO3-Bim axis and also the terminal unfolded protein response. Importantly, TAK-580 also enhanced lenalidomide-caused cytotoxicity and apoptosis in MM cells. Taken together, our results supply the rationale for TAK-580 monotherapy and/or treatment in conjunction with novel agents to enhance outcomes in patients with MM.Tovorafenib