The Rationale for the Dual-Targeting Therapy for RSK2 and AKT in Multiple Myeloma.
The Rationale for the Dual-Targeting Therapy for RSK2 and AKT in Multiple Myeloma.
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DOI：
10.3390/ijms23062919
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发表时间：
2022-03-08
影响因子：
5.6
通讯作者：
Kuroda J
中科院分区：
文献类型：
--
作者：
Isa R;Horinaka M;Tsukamoto T;Mizuhara K;Fujibayashi Y;Taminishi-Katsuragawa Y;Okamoto H;Yasuda S;Kawaji-Kanayama Y;Matsumura-Kimoto Y;Mizutani S;Shimura Y;Taniwaki M;Sakai T;Kuroda J
多发性骨髓瘤（MM）的特征是患者之间存在显著的细胞遗传学/分子异质性，甚至在单个患者中也存在克隆内多样性。我们以前证明，PDPK 1，一系列AGC激酶的主激酶，是普遍活跃的MM，并在细胞增殖和骨髓瘤细胞的细胞存活中起着关键作用，无论细胞遗传学和遗传异常的档案。本研究研究了MM中两种主要PDPK 1底物RSK 2和AKT双重阻断的治疗效果和作用机制。BI-D1870（RSK 2 N-末端激酶结构域（NTKD）抑制剂）和ipatasertib（AKT抑制剂）的联合治疗显示出对人MM衍生细胞系（HMCL）与活性RSK 2-NTKD和AKT的叠加协同抗肿瘤作用，通过增强BIM和BID激活的凋亡诱导。此外，RSK 2和AKT的双重阻断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HMCL中MYC、mTOR、STK 33、核糖体生物发生或可溶性因子的细胞外源性刺激。这些结果为RSK 2和AKT的双靶向策略提供了生物学和分子学基础，这可能克服MM中由于细胞遗传学/分子异质性而导致的治疗困难。
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.
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