Oncotarget

Research Papers:

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 _, Yuka Kitamura, Yoshihiko Nakamura, Hibiki Akashi, Yoshiaki Ogawa, Hiroshi Kawada and Kiyoshi Ando _

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Oncotarget. 2020; 11:3984-3997. https://doi.org/10.18632/oncotarget.27775

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Abstract

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

Correspondence to:

Rikio Suzuki,email: Rikio_Suzuki@tsc.u-tokai.ac.jp
Kiyoshi Ando,email: andok@keyaki.cc.u-tokai.ac.jp

Keywords: pan-RAF inhibitor; Bim; FOXO3a; bortezomib; lenalidomide

Received: January 12, 2020     Accepted: September 29, 2020     Published: November 03, 2020

Copyright: © 2020 Suzuki et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ABSTRACT

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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