B细胞淋巴瘤(BCL)是血液恶性肿瘤中最常见的疾病实体,具有各种遗传和分子上不同的亚型。在这项研究中,我们揭示了磷酸肌醇依赖性激酶-1(PDPK1)的阻断,AGC激酶的主激酶,在所有八种检测的BCL衍生细胞系中,通过细胞周期停滞和诱导凋亡诱导生长抑制,包括那些来自活化的B细胞样弥漫性大B细胞淋巴瘤(DLBCL),双表达式DLBCL,伯基特淋巴瘤,和滤泡性淋巴瘤.我们还证明,在这些细胞系中,RSK2,AKT,和S6K,但不是PLK1,SGK,或PKC,是PDPK1的主要下游治疗靶分子,RSK2在细胞存活和增殖中起核心作用,AKT和S6K作为PDPK1的下游效应子发挥辅助功能作用。根据这些结果,我们证实了TAS0612的抗淋巴瘤功效,TAS0612是总RSK的三联抑制剂,包括RSK2,AKT,和S6K,不仅在这些细胞系中,不管疾病亚型,而且在所有25个患者来源的各种疾病亚型的B淋巴瘤细胞。在分子水平上,TAS0612引起MYC和mTOR靶基因的显著下调,同时在这些细胞系中诱导肿瘤抑制因子TP53INP1蛋白。这些成果证明,同时阻断RSK2、AKT、和S6K,是PDPK1的关键下游底物,是BCLs各种疾病亚型的新型治疗靶标,并使TAS0612成为BCLs未来临床开发的有吸引力的候选药物。
B-cell lymphomas (BCLs) are the most common disease entity among hematological malignancies and have various genetically and molecularly distinct subtypes. In this study, we revealed that the blockade of phosphoinositide-dependent kinase-1 (PDPK1), the master kinase of AGC kinases, induces a growth inhibition via cell cycle arrest and the induction of apoptosis in all eight BCL-derived cell lines examined, including those from activated B-cell-like diffuse large B-cell lymphoma (DLBCL), double expressor DLBCL, Burkitt lymphoma, and follicular lymphoma. We also demonstrated that, in these cell lines, RSK2, AKT, and S6K, but not PLK1, SGK, or PKC, are the major downstream therapeutic target molecules of PDPK1 and that RSK2 plays a central role and AKT and S6K play subsidiary functional roles as the downstream effectors of PDPK1 in cell survival and proliferation. Following these results, we confirmed the antilymphoma efficacy of TAS0612, a triple inhibitor for total RSK, including RSK2, AKT, and S6K, not only in these cell lines, regardless of disease subtypes, but also in all 25 patient-derived B lymphoma cells of various disease subtypes. At the molecular level, TAS0612 caused significant downregulation of MYC and mTOR target genes while inducing the tumor suppressor TP53INP1 protein in these cell lines. These results prove that the simultaneous blockade of RSK2, AKT, and S6K, which are the pivotal downstream substrates of PDPK1, is a novel therapeutic target for the various disease subtypes of BCLs and line up TAS0612 as an attractive candidate agent for BCLs for future clinical development.