CDK12 tumor suppressor function and therapeutic targeting in newly developed mouse models of serous ovarian cancer

Adenocarcinoma of the ovary is the fifth leading cause of cancer death among American women. Most mortality results from high-grade serous ovarian carcinoma (HGS-OvCa)—a disease type resistant to conventional chemotherapy, and therein requiring urgent preclinical modeling for pharmaceutical testing. We generated a novel serous ovarian carcinoma model by employing Ovgp1-driven Cre recombinase to catalyze CRISPR-Cas9-medicated ablation of the Trp53, Rb1 and Nf1 tumor suppressor genes in the mouse ovary (m-sgPRN mice). The gene encoding cyclin dependent kinase 12 (CDK12) is among the most frequently inactivated in HGS-OvCa. Its loss corresponds with increased mortality, DNA damage (including tandem duplications) and tumor immunogenicity. Co-ablation of Cdk12 in the m-sgPRN model (m-sgPRN; Cdk12KO mice) accelerated tumor progression leading to bona fide HGS-OvCa, and early mortality. In a conventional (Cre-lox-medicated) Trp53/ Nf1/ Rb1 triple knockout model, Cdk12 ablation (PRN; Cdk12KO mice) effected immune infiltration characterized by CD3, CD8, CD4, and Granzyme B positivity like that seen in clinical HGS-OvCa. We observed recapitulation of this immunogenic phenotype—with corresponding sensitivity to immune checkpoint blockade—in a novel syngeneic allograft model derived from these animals. To screen for synthetic lethal interactions with Cdk12 loss, we conducted a CRISPR-Cas9 screen in PRN; Cdk12KO cell lines. The gene encoding CDK12 paralog CDK13 emerged as the most depleted, suggesting CDK13 could be targeted to promote paralog-induced synthetic lethality as previously demonstrated in CDK12-mutant prostate cancer. Indeed, m-sgPRN; Cdk12KO and PRN; Cdk12KO -derived cell lines exhibited enhanced sensitivity to the CDK13/12 degrader YJ1206. Our work defines CDK13-targeting as a novel treatment modality for CDK12-inactive HGS-OvCa while establishing biological resources for the in vivo modeling of this disease.