Tien Jean Ching-Yi, Zhai Yali, Wu Rong, Zhang Yuping, Chang Yu, Cheng Yunhui, Todd Abigail J, Wheeler Christina E, Li Shuqin, Mannan Rahul, Cheng Caleb, Magnuson Brian, Cruz Gabriel, Cao Yizhi, Mahapatra Somnath, Stolfi Carmine, Cao Xuhong, Su Fengyun, Wang Rui, Yang Jianzhang, Zhou Licheng, Qiao Yuanyuan, Xiao Lanbo, Cieslik Marcin, Wang Xiaoju, Wang Zhen, Chou Jonathan, Fearon Eric R, Ding Ke, Cho Kathleen R, Chinnaiyan Arul M
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109.
Department of Pathology, University of Michigan, Ann Arbor, MI 48109.
Proc Natl Acad Sci U S A. 2025 Jun 17;122(24):e2426909122. doi: 10.1073/pnas.2426909122. Epub 2025 Jun 12.
Ovarian cancer is the sixth leading cause of cancer death among American women, with most fatalities attributable to tubo-ovarian high-grade serous carcinoma (HGSC). This malignancy usually develops resistance to conventional chemotherapy, underscoring the need for robust preclinical models to guide the development of novel therapies. Here, we introduce an HGSC mouse model generated via -driven Cre recombinase effecting CRISPR/Cas9-mediated deletion of , and tumor suppressors in mouse oviductal epithelium ( model). Cyclin-dependent kinase 12 (CDK12) inactivation-frequently observed in human HGSC-is associated with poorer outcomes, DNA damage accumulation (including tandem duplications), and increased tumor immunogenicity. In our system, coablation of () recapitulated hallmark features of HGSC, while accelerating tumor progression and reducing survival. In a conventional (Cre-lox-mediated) triple knockout model with concurrent ablation (; mice), we observed T cell-rich immune infiltrates mirroring those seen clinically. We established both models as subcutaneous or intraperitoneal syngeneic allografts of -inactivated HGSC that exhibited sensitivity to immune checkpoint blockade. Furthermore, a CRISPR/Cas9 synthetic lethality screen in -derived cell lines identified CDK13-an essential paralog of CDK12-as the most depleted candidate, confirming a previously reported synthetic lethal interaction. Pharmacologic CDK13/12 degradation (employing YJ1206) demonstrated enhanced efficacy in cell lines derived from both and ; models. Our results define as a key tumor suppressor in tubo-ovarian HGSC and highlight CDK13 targeting as a promising therapeutic approach in -inactive disease. Additionally, we have established valuable in vivo resources to facilitate further investigation and drug development in this challenging malignancy.
卵巢癌是美国女性癌症死亡的第六大主要原因，大多数死亡归因于输卵管卵巢高级别浆液性癌（HGSC）。这种恶性肿瘤通常会对传统化疗产生耐药性，这突出表明需要强大的临床前模型来指导新型疗法的开发。在此，我们介绍一种通过驱动Cre重组酶产生的HGSC小鼠模型，该重组酶可实现CRISPR/Cas9介导的小鼠输卵管上皮中、和肿瘤抑制基因的缺失（模型）。细胞周期蛋白依赖性激酶12（CDK12）失活——在人类HGSC中经常观察到——与较差的预后、DNA损伤积累（包括串联重复）以及肿瘤免疫原性增加有关。在我们的系统中，（）的共同消融概括了HGSC的标志性特征，同时加速了肿瘤进展并缩短了生存期。在具有同时消融（；小鼠）的传统（Cre-lox介导）三重敲除模型中，我们观察到富含T细胞的免疫浸润与临床所见相似。我们将这两种模型都建立为对免疫检查点阻断敏感的失活HGSC的皮下或腹腔内同基因异体移植模型。此外，在源自的细胞系中进行的CRISPR/Cas9合成致死筛选确定CDK13——CDK12的一个必需旁系同源物——为最缺失的候选基因，证实了先前报道的合成致死相互作用。药理学上的CDK13/12降解（使用YJ1206）在源自和；模型的细胞系中显示出增强的疗效。我们的结果将定义为输卵管卵巢HGSC中的关键肿瘤抑制基因，并突出了靶向CDK13作为失活疾病中有前景的治疗方法。此外，我们已经建立了有价值的体内资源，以促进对这种具有挑战性的恶性肿瘤的进一步研究和药物开发。
