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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE284088 | GEO | 2025/05/23

REPOSITORIES: GEO