Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
Department of Drug Discovery Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
Int J Mol Sci. 2022 Mar 8;23(6):2919. doi: 10.3390/ijms23062919.
Multiple myeloma (MM) is characterized by remarkable cytogenetic/molecular heterogeneity among patients and intraclonal diversity even in a single patient. We previously demonstrated that PDPK1, the master kinase of series of AGC kinases, is universally active in MM, and plays pivotal roles in cell proliferation and cell survival of myeloma cells regardless of the profiles of cytogenetic and genetic abnormalities. This study investigated the therapeutic efficacy and mechanism of action of dual blockade of two major PDPK1 substrates, RSK2 and AKT, in MM. The combinatory treatment of BI-D1870, an inhibitor for N-terminal kinase domain (NTKD) of RSK2, and ipatasertib, an inhibitor for AKT, showed the additive to synergistic anti-tumor effect on human MM-derived cell lines (HMCLs) with active RSK2-NTKD and AKT, by enhancing apoptotic induction with BIM and BID activation. Moreover, the dual blockade of RSK2 and AKT exerted robust molecular effects on critical gene sets associated with myeloma pathophysiologies, such as those with MYC, mTOR, STK33, ribosomal biogenesis, or cell-extrinsic stimuli of soluble factors, in HMCLs. These results provide the biological and molecular rationales for the dual-targeting strategy for RSK2 and AKT, which may overcome the therapeutic difficulty due to cytogenetic/molecular heterogeneity in MM.
多发性骨髓瘤（MM）的特点是患者之间存在显著的细胞遗传学/分子异质性，即使在单个患者中也存在克隆内多样性。我们之前证明，PDK1 是一系列 AGC 激酶的主激酶，在 MM 中普遍活跃，并且无论细胞遗传学和遗传异常的特征如何，在骨髓瘤细胞的增殖和存活中都发挥着关键作用。本研究探讨了双重阻断两种主要 PDK1 底物（RSK2 和 AKT）在 MM 中的治疗效果和作用机制。RSK2 的 N 端激酶结构域（NTKD）抑制剂 BI-D1870 和 AKT 抑制剂 ipatasertib 的联合治疗对具有活性 RSK2-NTKD 和 AKT 的人 MM 衍生细胞系（HMCL）表现出相加至协同的抗肿瘤作用，通过激活 BIM 和 BID 增强凋亡诱导。此外，双重阻断 RSK2 和 AKT 在 HMCL 中对与骨髓瘤病理生理学相关的关键基因集产生了强大的分子效应，例如那些与 MYC、mTOR、STK33、核糖体生物发生或细胞外可溶性因子刺激相关的基因集。这些结果为 RSK2 和 AKT 的双重靶向策略提供了生物学和分子基础，这可能克服由于 MM 中的细胞遗传学/分子异质性而导致的治疗困难。
