The dysregulation of cyclin-dependent kinase 12(CDK12),which may result from genomic alterations or modulation by upstream effectors,is implicated in cancer oncogenesis and progression.CDK12 overexpression or activati...The dysregulation of cyclin-dependent kinase 12(CDK12),which may result from genomic alterations or modulation by upstream effectors,is implicated in cancer oncogenesis and progression.CDK12 overexpression or activation is sufficient to induce tumor initiation,recurrence,and therapeutic resistance.However,CDK12 may also exert tumor-suppressive functions in a context-dependent manner.Therefore,caution is warranted when targeting CDK12 in future clinical trials.A comprehensive elucidation of the dual roles and underlying mechanisms of CDK12 in carcinogenesis is urgently needed to advance precision oncology.This review provides an overview of the current understanding of the dysregulation and biological roles of CDK12 in cancer.Subsequently,we systematically summarize the functions and mechanisms of the oncogenic and tumor-suppressive roles of CDK12 in different contexts.Finally,we discuss the potential of CDK12 as a novel therapeutic target and its implications in clinical oncology,offering insights into future directions for innovative cancer treatment strategies.展开更多
CDK12是一种参与细胞周期调控、前体mRNA剪接及DNA损伤同源重组修复的重要转录因子,其丢失可导致基因组不稳定性及串联重复的增加。大约4%~11%的前列腺癌(prostate cancer,PCa)患者中存在CDK12基因突变,并且其突变率在转移性去势抵抗型...CDK12是一种参与细胞周期调控、前体mRNA剪接及DNA损伤同源重组修复的重要转录因子,其丢失可导致基因组不稳定性及串联重复的增加。大约4%~11%的前列腺癌(prostate cancer,PCa)患者中存在CDK12基因突变,并且其突变率在转移性去势抵抗型前列腺癌(metastatic castration-resistance prostate cancer,mCRPC)患者当中比例更高。尽管CDK12基因丢失或抑制可能会损伤DNA同源重组修复途径中的特定基因,但PARP抑制剂却对存在CDK12丢失的PCa患者疗效欠佳。近年来有研究报道指出PCa中CDK12基因丢失是一种新的分子亚型,其具有较高比例的新抗原融合、免疫浸润及PD-1/PD-L1抑制剂应答率高等特点。但目前关于该基因的致癌作用和临床特征,尤其在PCa当中仍不明确。因此近期发表于《European Urology》杂志上(Pan-cancer analysis of CDK12 alterations identifies a subset of prostate cancers with distinct genomic and clinical characteristics)的论文就全肿瘤CDK12突变情况及其PCa特殊亚型的临床特征进行了报道。展开更多
基金supported by the National Natural Science Foundation of China(Grant Nos.:82260718,82460716 and 82111530101)Natural Science Foundation of Jiangxi Province,China(Grant Nos.:20224BAB216121,20232BAB216137 and 20242BAB25579)+1 种基金Jiangxi Provincial Thousand Talents Training Program for High Level Entrepreneurial and Innovative Talents,China(Program No.:jxsq2019201106)Ganzhou“Taking the Lead”Youth Project of Technology Innovation Empowerment(Project No.:JBGS20230001).
文摘The dysregulation of cyclin-dependent kinase 12(CDK12),which may result from genomic alterations or modulation by upstream effectors,is implicated in cancer oncogenesis and progression.CDK12 overexpression or activation is sufficient to induce tumor initiation,recurrence,and therapeutic resistance.However,CDK12 may also exert tumor-suppressive functions in a context-dependent manner.Therefore,caution is warranted when targeting CDK12 in future clinical trials.A comprehensive elucidation of the dual roles and underlying mechanisms of CDK12 in carcinogenesis is urgently needed to advance precision oncology.This review provides an overview of the current understanding of the dysregulation and biological roles of CDK12 in cancer.Subsequently,we systematically summarize the functions and mechanisms of the oncogenic and tumor-suppressive roles of CDK12 in different contexts.Finally,we discuss the potential of CDK12 as a novel therapeutic target and its implications in clinical oncology,offering insights into future directions for innovative cancer treatment strategies.
文摘CDK12是一种参与细胞周期调控、前体mRNA剪接及DNA损伤同源重组修复的重要转录因子,其丢失可导致基因组不稳定性及串联重复的增加。大约4%~11%的前列腺癌(prostate cancer,PCa)患者中存在CDK12基因突变,并且其突变率在转移性去势抵抗型前列腺癌(metastatic castration-resistance prostate cancer,mCRPC)患者当中比例更高。尽管CDK12基因丢失或抑制可能会损伤DNA同源重组修复途径中的特定基因,但PARP抑制剂却对存在CDK12丢失的PCa患者疗效欠佳。近年来有研究报道指出PCa中CDK12基因丢失是一种新的分子亚型,其具有较高比例的新抗原融合、免疫浸润及PD-1/PD-L1抑制剂应答率高等特点。但目前关于该基因的致癌作用和临床特征,尤其在PCa当中仍不明确。因此近期发表于《European Urology》杂志上(Pan-cancer analysis of CDK12 alterations identifies a subset of prostate cancers with distinct genomic and clinical characteristics)的论文就全肿瘤CDK12突变情况及其PCa特殊亚型的临床特征进行了报道。
