Anti-tumor activity of the pan-RAF inhibitor TAK-580 in combination with KPT-330 (selinexor) in multiple myeloma
Anti-tumor activity of the pan-RAF inhibitor TAK-580 in combination with KPT-330 (selinexor) in multiple myeloma
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DOI：
10.1007/s12185-021-03244-1
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发表时间：
2021-11
影响因子：
2.1
通讯作者：
R. Suzuki;Yuka Kitamura;Daisuke Ogiya;Y. Ogawa;H. Kawada;K. Ando
中科院分区：
文献类型：
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作者：
R. Suzuki;Yuka Kitamura;Daisuke Ogiya;Y. Ogawa;H. Kawada;K. Ando
RAS/RAF/MEK/ERK通路抑制剂对包括多发性骨髓瘤（MM）在内的各种肿瘤类型表现出显著的抗肿瘤作用，预计它们将在精准医学中发挥关键作用。XPO 1抑制剂KPT-330与其他新药联合治疗复发性/难治性MM（RRMM）也显示出有希望的疗效。在这项研究中，我们探索了泛RAF抑制剂TAK-580和KPT-330联合使用的抗肿瘤作用。重要的是，TAK-580增强了人骨髓瘤细胞系和RRMM患者的原代骨髓瘤细胞中KPT-330诱导的细胞毒性和细胞凋亡。此外，TAK-580和KPT-330协同抑制MM细胞中的细胞核磷酸化FOXO 3a并增强细胞质磷酸化FOXO 3a，导致细胞质Bim表达增强，最终导致细胞凋亡。这表明TAK-580主要通过FOXO 3a-Bim轴增强KPT-330诱导的细胞毒性和细胞凋亡。此外，即使在存在IGF-1的情况下，TAK-580也可增强KPT-330对MM细胞的细胞毒性。总之，我们的结果表明，泛RAF抑制剂和XPO 1抑制剂的组合是治疗MM的潜在治疗选择。
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.