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

• DOI: 10.1158/2767-9764.c.7795994
• Publication Date: 2025-04-30T23:23:55Z
• Authors: Zelei Yang; Saie Mogre; Hyeji Jun; Ruiyang He; Sneha Ghosh Chaud...; Upendra Raj Bhatt...; Shannan J. Ho Sui; Ursula A. Matulonis; Suzan Lazo; Aniket Shetty; Amy Cameron; Quang-Dé Nguyen; Sarah J. Hill
• Keywords: Stratification (seeds); Profiling (computer programming)

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