Anti-tumor activities of the new oral pan-RAF inhibitor, TAK-580, used as monotherapy or in combination with novel agents in multiple myeloma
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Rikio Suzuki1, Yuka Kitamura2, Yoshihiko Nakamura2, Hibiki Akashi1, Yoshiaki Ogawa1, Hiroshi Kawada1 and Kiyoshi Ando1,2
1 Department of Hematology/Oncology, Tokai University School of Medicine, Isehara, Kanagawa, Japan
2 Center for Regenerative Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan
|Rikio Suzuki,||email:||[email protected]|
|Kiyoshi Ando,||email:||[email protected]|
Keywords: pan-RAF inhibitor; Bim; FOXO3a; bortezomib; lenalidomide
Received: January 12, 2020 Accepted: September 29, 2020 Published: November 03, 2020
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.
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