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Anti-tumor activity of the pan-RAF inhibitor TAK-580 in combination with KPT-330 (selinexor) in multiple myeloma

RAS/RAF/MEK/ERK pathway inhibitors exhibit significant anti-tumor effects against various tumor types, including multiple myeloma (MM), and they are predicted to play a pivotal role in precision medicine. The XPO1 inhibitor KPT-330 has also exhibited promising efficacy in combination with other novel drugs in treating relapsed/refractory MM (RRMM). In this study, we explored the anti-tumor effects of a combination of the pan-RAF inhibitor TAK-580 and KPT-330. Importantly, TAK-580 enhanced KPT-330-induced cytotoxicity and apoptosis in human myeloma cell lines and primary myeloma cells from RRMM patients. Moreover, TAK-580 and KPT-330 synergistically inhibited nuclear phospho-FOXO3a and enhanced cytoplasmic phospho-FOXO3a in MM cells, leading to cytoplasmic enhanced Bim expression and finally apoptosis. This indicates that TAK-580 enhances KPT-330-induced cytotoxicity and apoptosis primarily via the FOXO3a-Bim axis. In addition, TAK-580 enhanced the cytotoxicity of KPT-330 against MM cells even in the presence of IGF-1. Taken together, our results demonstrate that a combination of pan-RAF inhibitor and XPO1 inhibitor is a potential therapeutic option in treating MM.

 

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This study suggests that a combination of the pan-RAF inhibitor TAK-580 and XPO1 inhibitor KPT-330 exhibits significant anti-tumor effects against multiple myeloma (MM). The study found that TAK-580 enhanced KPT-330-induced cytotoxicity and apoptosis in human myeloma cell lines and primary myeloma cells from relapsed/refractory MM (RRMM) patients. This synergistic effect was mediated via the FOXO3a-Bim axis, as TAK-580 and KPT-330 synergistically inhibited nuclear phospho-FOXO3a and enhanced cytoplasmic phospho-FOXO3a in MM cells, leading to cytoplasmic enhanced Bim expression and finally apoptosis.

Importantly, the combination of TAK-580 and KPT-330 enhanced cytotoxicity even in the presence of IGF-1, indicating that this combination could be a potential therapeutic option for treating MM. These findings suggest that targeting multiple pathways simultaneously may be an effective strategy for treating MM and other tumor types, and that precision medicine approaches could benefit from such combinations.

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S7121 Tovorafenib (MLN2480) Tovorafenib (MLN2480, BIIB-024, TAK580, AMG-2112819, BSK1369, DAY-101) is an oral, selective pan-Raf kinase inhibitor in chinical trials.

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