细胞周期蛋白依赖性激酶4/6抑制剂曲拉西利抗肿瘤作用机制及临床研究进展  

Mechanisms and clinical research progress in oncotherapy of trilaciclib,a cyclin-dependent kinase 4/6 inhibitor

作　　者：郑雪晴 张力[1] 张晓彤[1] ZHENG Xue-qing;ZHANG Li;ZHANG Xiao-tong(Department of Pulmonary and Critical Care Medicine,Peking Union Medical College Hospital,Chinese Academy of Medical Science&Peking Union Medical College,Beijing 100730,China)

机构地区：[1]中国医学科学院北京协和医学院北京协和医院呼吸与危重症医学科,北京100730

出　　处：《中国新药杂志》2023年第23期2329-2338,共10页Chinese Journal of New Drugs

摘　　要：细胞周期调控异常在肿瘤发生发展过程中发挥着关键作用。细胞周期蛋白依赖性激酶(cyclin-dependent kinase, CDK)家族负责细胞周期调控,其中CDK4和CDK6的活化使细胞从G1期进入S期启动有丝分裂。CDK4/6的过度激活与肿瘤发生密切相关,是抗肿瘤的可能靶点之一。CDK4/6抑制剂可以通过作用于细胞周期阻滞肿瘤生长,同时影响肿瘤微环境、增强免疫活性,辅助抗肿瘤治疗。曲拉西利是一种小分子、高效、选择性、可逆的CDK4/6抑制剂。曲拉西利在化疗前给药可将骨髓中的造血干细胞和髓系及淋巴系祖细胞暂时阻滞于G1期,降低化疗引起的细胞毒性损伤,从而保护骨髓及免疫功能。2021年2月,曲拉西利已被美国FDA首次批准在广泛期小细胞肺癌(extensive stage small-cell lung cancer, ES-SCLC)的含铂/依托泊苷或含拓扑替康的化疗方案前使用,以减少成人患者化疗引起的骨髓抑制发生率。2022年7月,国家药品监督管理局也批准了曲拉西利应用于既往未接受过系统性化疗的ES-SCLC患者。另外,研究表明曲拉西利联合化疗可显著延长转移性三阴乳腺癌患者的生存期,其他曲拉西利相关临床研究仍在进行中。本文系统总结了曲拉西利的抗肿瘤作用机制,并梳理了曲拉西利的临床前及临床研究,以期为临床应用及未来研究提供参考。Control of cell cycle progression plays a significant role in tumor development.The cyclindependent kinase(CDK)family governs cell cycle progression,and the activations of CDK4 and CDK6 allow cells to transit from Gl phase to S phase to start mitosis.Overactivation of CDK4/6 is closely related to tumor progression,thus CDK4/6 can be used as a potential target of oncotherapy.CDK4/6 inhibitors can not only arrest the tumor cells at Gl phase to prevent tumor overgrowth,but also affect the tumor microenvironment and enhance immune activity.Trilaciclib is a small-molecule CDK4/6 inhibitor,which is highly efficient,selective and reversible.Trilaciclib administrated before chemotherapy can temporarily block the hematopoietic stem cells and progenitor cells in bone marrow at G1 phase to reduce the cytotoxic damage caused by chemotherapy,thus protecting bone marrow and the immune system.Trilaciclib was first approved by FDA in the United States in February 2021 for extensive stage small cell lung cancer(ES-SCLC)before platinum/etoposide or topotecan chemotherapy to reduce the incidences of myelosuppression in adult patients.In July 2022,National Medical Products Administration(NMPA)also approved the administration of trilaciclib in patients with ES-SCLC who had not previously received systemic chemotherapy.In addition,the positive effects of trilaciclib on overall survival(OS)were observed in patients with triple-negative breast cancer(TNBC)treated with chemotherapy.Other clinical studies related to trilaciclib were still ongoing.This review summarizes the anti-tumor mechanisms of trilaciclib and the relative preclinical and clinical studies,aiming to provide further reference for clinical application and future research.

关 键 词：曲拉西利 肿瘤治疗 化疗药物 骨髓抑制 免疫调节 

分 类 号：R979.1[医药卫生—药品]