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

doi:10.18632/oncotarget.27775

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.

Highlights

Multiple myeloma (MM) is a B-cell malignancy characterized by clonal proliferation of abnormal plasma cells driven by genetic abnormalities in the specific bone marrow microenvironment and niche, excess production of monoclonal protein in the serum and/or urine, osteolytic bone lesions, and immunodeficiency [1, 2]
The rat sarcoma (RAS)-raf murine sarcoma viral oncogene homolog (RAF)-mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) signaling pathway plays an important role in tumorigenesis, cell proliferation, inhibition of apoptosis, and drug resistance [19, 20]
The combination of a panRAF inhibitor and a MEK inhibitor shows an excellent effect on patients with this mutation [21, 22], has already been clinically applied [23], and is considered to be a successful example of inhibiting the RAS-RAF-MEKERK pathway

Summary

Introduction

Multiple myeloma (MM) is a B-cell malignancy characterized by clonal proliferation of abnormal plasma cells driven by genetic abnormalities in the specific bone marrow microenvironment and niche, excess production of monoclonal protein in the serum and/or urine, osteolytic bone lesions, and immunodeficiency [1, 2]. A revolution in treatment strategies has prolonged the survival of patients with both newly diagnosed and relapsed/refractory MM. These treatments include high-dose chemotherapy and stem cell transplantation; immunotherapies including two monoclonal antibodies (daratumumab and elotuzumab), bi-specific T-cell engagers, and chimeric antigen receptor therapy; and novel therapies including bortezomib (BTZ), thalidomide, and lenalidomide (LEN) [1, 3, 4]. RAS pathway-driven cancers, including MM, are aggressive and are refractory to current therapeutic interventions (mainly RAF and MEK inhibitors), typically due to narrow therapeutic windows, paradoxical pathway activation, feedback induction of phosphatidylinositol-3 kinase/Akt signaling, and/or drug resistance, demonstrating an unmet medical need [10]. TAK-580 is expected to be a promising pan-RAF inhibitor

Methods

Results

Conclusion