Multiple myeloma (MM) remains a difficult-to-treat disease even with the latest therapeutic advances due to the complex, overlapping, and heterogeneous cytogenetic, genetic, and molecular abnormalities. To address this challenging problem, we previously identified the universal and critical roles of RSK2 and AKT, the effector signaling molecules downstream of PDPK1, regardless of cytogenetic and genetic profiles. Based on this, in this study, we investigated the anti-myeloma potency of TAS0612, a triple inhibitor against RSK, including RSK2, AKT, and S6K. Treatment with TAS0612 exerted the anti-proliferative effect via cell cycle blockade and the induction of apoptosis in human myeloma-derived cell lines (HMCLs) with diverse cytogenetic and genetic profiles. Ex vivo treatment with TAS0612 also significantly reduced the viability of patient-derived primary myeloma cells with diverse cytogenetic profiles. TAS0612 simultaneously caused the upregulation of several tumor suppressor genes, modulated prognostic genes according to the MMRF CoMMpass data, and downregulated a series of Myc- and mTOR-related genes. Moreover, the combination of TAS0612 with venetoclax (VEN) showed the synergy in inducing apoptosis in HMCLs irrespective of the t(11;14) translocation status. TAS0612 alone and combined with VEN are new potent candidate therapeutic strategies for MM, regardless of cytogenetic/genetic profiles, facilitating its future clinical development.

多发性骨髓瘤 （MM） 由于其复杂、重叠和异质性的细胞遗传学、遗传学和分子异常，即使有最新的治疗进展，仍然是一种难以治疗的疾病。为了解决这一具有挑战性的问题，我们之前确定了 RSK2 和 AKT 的普遍和关键作用，它们是 PDPK1 下游的效应信号分子，与细胞遗传学和遗传特征无关。基于此，在这项研究中，我们研究了 TAS0612 的抗骨髓瘤效力， 是一种针对 RSK 的三重抑制剂，包括 RSK2、AKT 和 S6K。TAS0612 治疗通过细胞周期阻断和诱导具有不同细胞遗传学和遗传谱的人骨髓瘤衍生细胞系 （HMCLs） 细胞凋亡发挥抗增殖作用。用 TAS0612 进行离体治疗也显著降低了具有不同细胞遗传学特征的患者来源的原发性骨髓瘤细胞的活力。TAS0612 同时导致几个肿瘤抑制基因的上调，根据 MMRF CoMMpass 数据调节预后基因，并下调一系列 Myc 和 mTOR 相关基因。此外，TAS0612 与维奈托克 （VEN） 的组合显示出诱导 HMCLs 细胞凋亡的协同作用，与 t（11;14） 易位状态。TAS0612单独使用和与 VEN 联合是 MM 的新型有效候选治疗策略，无论细胞遗传学/遗传特征如何，都有助于其未来的临床开发。