Functional Profiling of p53 and RB Cell Cycle Regulatory Proficiency Suggests Mechanism-Driven Molecular Stratification in Endometrial Carcinoma.

ABSTRACT: In the United States, Endometrial carcinoma (EC) is the most frequently occurring gynecologic cancer. Many ECs harbor mutations in cell cycle regulatory genes including TP53 and RB1, amongst others. RB and p53 both regulate the G1/S transition while p53 also regulates the G2/M transition and mitotic progression, all of which rely on targetable regulatory kinases. It is likely that many ECs harbor targetable defects in some aspect of cell cycle regulation, but there has been no profiling of p53- or RB- linked cell cycle functional capacity and corresponding therapeutic vulnerabilities in EC cells. Here, we utilize functional and transcriptomic assays on a panel of EC cell lines and patient-derived organoids to characterize the p53 and RB cell cycle regulatory proficiency and linked therapeutic vulnerabilities in EC. We show that TP53 genomic and functional status has poor predictive capacity for EC therapeutic response. Rather, proper RB regulation correlates with response to G1/S targeting CDK4/6 inhibitors, and dysfunction in regulation of mitotic progression correlates with response to Aurora kinase B inhibitors. A subset of TP53 mutant ECs are RB1 wild type, express RB protein, have intact RB regulation, and are sensitive to CDK4/6 inhibitors, suggesting that excluding patients from emerging CDK4/6 inhibitor trials based on aggressive histology or TP53 status should be reconsidered. These findings were validated in vivo in xenograft models. These results can expand current EC molecular stratification to include mechanism-driven subtypes and suggest clinical trials of novel targeted therapies based on biologic understanding for advanced or recurrent EC patients. SIGNIFICANCE: We show novel cell cycle regulatory molecular classifications and therapeutic targets for endometrial carcinoma. Intact RB regulation and mitotic progression regulatory defects correlate with CDK4/6 and Aurora kinase B inhibitor sensitivity respectively.