Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, 05505, South Korea.
Department of Oncology, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, 05505, South Korea.
Sci Rep. 2019 May 10;9(1):7193. doi: 10.1038/s41598-019-43760-z.
Mantle cell lymphoma (MCL) is typically an aggressive and rare form of non-Hodgkin lymphoma (NHL) with a poor prognosis despite recent advances in immunochemotherapy and targeted therapeutics against NHL. New therapeutic agents are needed for MCL. In this study, we generated a potent inhibitor of cyclin-dependent kinase 7 (CDK7), designated QS1189, and confirmed its anti-cancer effects towards MCL and other lymphomas. QS1189 was highly selective for CDK7 and showed potent anticancer effects in MCL compared to other targeted therapeutic agents, such as ibrutinib and venetoclax. Consistent with a conventional CDK7 inhibitor, QS1189 treatment significantly decreased phosphorylation of the carboxyl-terminal domain of RNA polymerase II and transcription-associated genes. QS1189 induced cell cycle arrest at the G2/M phase and apoptosis. Interestingly, QS1189 overcame the acquired resistance to venetoclax, which is mediated by Bcl-xL. Similarly, QS1189 showed potent tumour cell growth inhibition of various lymphomas. Thus, CDK7 might be a suitable therapeutic target for inhibiting lymphoma, and QS1189 is a promising therapeutic option for various lymphomas and cells with acquired resistance to targeted therapy.
套细胞淋巴瘤（MCL）是一种侵袭性和罕见的非霍奇金淋巴瘤（NHL），尽管最近在 NHL 的免疫化疗和靶向治疗方面取得了进展，但预后仍然较差。MCL 需要新的治疗药物。在这项研究中，我们生成了一种有效的细胞周期蛋白依赖性激酶 7（CDK7）抑制剂，命名为 QS1189，并证实了其对 MCL 和其他淋巴瘤的抗癌作用。QS1189 对 CDK7 具有高度选择性，与其他靶向治疗药物（如伊布替尼和维奈托克）相比，对 MCL 具有更强的抗癌作用。与传统的 CDK7 抑制剂一致，QS1189 治疗显著降低了 RNA 聚合酶 II 羧基末端结构域和转录相关基因的磷酸化。QS1189 诱导细胞周期在 G2/M 期停滞和凋亡。有趣的是，QS1189 克服了对 venetoclax 的获得性耐药，这种耐药是由 Bcl-xL 介导的。同样，QS1189 对各种淋巴瘤的肿瘤细胞生长具有很强的抑制作用。因此，CDK7 可能是抑制淋巴瘤的一个合适的治疗靶点，QS1189 是治疗各种淋巴瘤和对靶向治疗产生获得性耐药的细胞的一种有前途的选择。
