Maegawa Saori, Chinen Yoshiaki, Shimura Yuji, Tanba Kazuna, Takimoto Tomoko, Mizuno Yoshimi, Matsumura-Kimoto Yayoi, Kuwahara-Ota Saeko, Tsukamoto Taku, Kobayashi Tsutomu, Horiike Shigeo, Taniwaki Masafumi, Kuroda Junya
Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan; Department of Molecular Diagnostics and Therapeutics, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan.
Exp Hematol. 2018 Mar;59:72-81.e2. doi: 10.1016/j.exphem.2017.12.006. Epub 2017 Dec 26.
Mantle cell lymphoma (MCL) is a relatively rare subtype of B-cell non-Hodgkin lymphoma (NHL) that has a poor prognosis despite recent advances in immunochemotherapy and molecular targeted therapeutics against NHL. Therefore, the development of a new therapeutic strategy for MCL is urgently needed. In this study, we show for the first time that 3-phosphoinositide-dependent protein kinase 1 (PDPK1), an oncogenic serine-threonine protein kinase, is commonly expressed in its phosphorylated active form in patient-derived tumor cells of various types of B-cell NHL cells, including diffuse large B-cell lymphoma, follicular lymphoma, and MCL. Blockade of PDPK1 activity by small-molecule inhibitors specific for PDPK1 (BX-912 and GSK2334470) or by RNA interference exerted antiproliferative effects in all four MCL-derived cell lines examined and these growth-inhibitory effects were mediated by both induction of apoptosis and G/M cell cycle blockade. In addition, blockade of PDPK1 led to inactivation of its downstream effector kinase RSK2, but not AKT, suggesting the importance of the PDPK1/RSK2 signaling pathway in the proliferation and survival of MCL cells. Finally, when combined with anticancer agents, including genotoxic agents, a proteasome inhibitor, and a BH3 mimetic in vitro, the PDPK1 inhibitor BX-912 showed additive growth-inhibitory effects against MCL-derived cell lines in most settings. In particular, the combination of BX-912 and ABT-263, a BH3 mimetic, resulted in the enhancement of the induction of apoptosis. In conclusion, our results suggest that PDPK1 is a potential novel therapeutic target in MCL and indicate that clinical development of PDPK1-targeted therapy for MCL is desirable.
套细胞淋巴瘤（MCL）是B细胞非霍奇金淋巴瘤（NHL）中一种相对罕见的亚型，尽管针对NHL的免疫化疗和分子靶向治疗取得了最新进展，但其预后仍然很差。因此，迫切需要开发一种针对MCL的新治疗策略。在本研究中，我们首次表明，3-磷酸肌醇依赖性蛋白激酶1（PDPK1），一种致癌的丝氨酸-苏氨酸蛋白激酶，在包括弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤和MCL在内的各种类型B细胞NHL细胞的患者来源肿瘤细胞中通常以其磷酸化活性形式表达。用对PDPK1特异的小分子抑制剂（BX-912和GSK2334470）或通过RNA干扰阻断PDPK1活性，在所检测的所有四种MCL来源的细胞系中均发挥了抗增殖作用，并且这些生长抑制作用是由诱导凋亡和G/M期细胞周期阻滞介导的。此外，阻断PDPK1导致其下游效应激酶RSK2失活，但不影响AKT，这表明PDPK1/RSK2信号通路在MCL细胞的增殖和存活中具有重要作用。最后，当在体外与包括基因毒性药物、蛋白酶体抑制剂和BH3模拟物在内的抗癌药物联合使用时，PDPK1抑制剂BX-912在大多数情况下对MCL来源的细胞系显示出相加的生长抑制作用。特别是，BX-912与BH3模拟物ABT-263联合使用可增强凋亡诱导作用。总之，我们的结果表明PDPK1是MCL中一个潜在的新型治疗靶点，并表明针对MCL的PDPK1靶向治疗的临床开发是可取的。
