Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, People's Republic of China; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, College of Pharmacy, Jinan University, Guangzhou 511400, People's Republic of China.
Cell Rep Med. 2024 Oct 15;5(10):101758. doi: 10.1016/j.xcrm.2024.101758. Epub 2024 Oct 4.
Biallelic loss of cyclin-dependent kinase 12 (CDK12) defines a metastatic castration-resistant prostate cancer (mCRPC) subtype. It remains unclear, however, whether CDK12 loss drives prostate cancer (PCa) development or uncovers pharmacologic vulnerabilities. Here, we show Cdk12 ablation in murine prostate epithelium is sufficient to induce preneoplastic lesions with lymphocytic infiltration. In allograft-based CRISPR screening, Cdk12 loss associates positively with Trp53 inactivation but negatively with Pten inactivation. Moreover, concurrent Cdk12/Trp53 ablation promotes proliferation of prostate-derived organoids, while Cdk12 knockout in Pten-null mice abrogates prostate tumor growth. In syngeneic systems, Cdk12/Trp53-null allografts exhibit luminal morphology and immune checkpoint blockade sensitivity. Mechanistically, Cdk12 inactivation mediates genomic instability by inducing transcription-replication conflicts. Strikingly, CDK12-mutant organoids and patient-derived xenografts are sensitive to inhibition or degradation of the paralog kinase, CDK13. We therein establish CDK12 as a bona fide tumor suppressor, mechanistically define how CDK12 inactivation causes genomic instability, and advance a therapeutic strategy for CDK12-mutant mCRPC.
双等位基因缺失细胞周期蛋白依赖性激酶 12（CDK12）定义了转移性去势抵抗性前列腺癌（mCRPC）亚型。然而，尚不清楚 CDK12 缺失是否驱动前列腺癌（PCa）的发展或揭示药物敏感性。在这里，我们表明 CDK12 在小鼠前列腺上皮中的缺失足以诱导具有淋巴细胞浸润的癌前病变。在基于同种异体移植物的 CRISPR 筛选中，Cdk12 缺失与 Trp53 失活呈正相关，但与 Pten 失活呈负相关。此外，同时 Cdk12/Trp53 缺失会促进前列腺源性类器官的增殖，而在 Pten 缺失的小鼠中敲除 Cdk12 则会阻断前列腺肿瘤的生长。在同种异体系统中，Cdk12/Trp53 缺失的同种异体移植物表现出腔上皮形态和免疫检查点阻断敏感性。在机制上，Cdk12 的失活通过诱导转录-复制冲突导致基因组不稳定性。引人注目的是，CDK12 突变的类器官和患者来源的异种移植物对 CDK13 的抑制或降解敏感。我们确立了 CDK12 作为一种真正的肿瘤抑制因子，从机制上定义了 CDK12 失活如何导致基因组不稳定，并为 CDK12 突变的 mCRPC 提供了一种治疗策略。
