Abstract 1643: Establishing rational combination strategies with selective CBP degraders in solid tumor indications

Abstract The paralog lysine acetyltransferases CREB binding protein (CBP) and E1A binding protein P300 (EP300) function as transcriptional coactivators that regulate diverse cellular programs. Mutations in CBP and EP300 have been implicated in the biology of various cancer types. The bidirectional synthetic lethal relationship between these paralogs in tumor cells highlights a therapeutic opportunity in targeting CBP selectively in EP300-mutant cancers. We have previously demonstrated that our selective CBP degraders have potent antiproliferative activity in EP300-mutant cancers through both in vitro assays and cell line-derived xenograft models when used as a single agent. We have now expanded our studies to explore strategies for combination treatment with approved chemotherapies to enhance tumor growth inhibition. Here, we demonstrate that our selective and potent CBP degrader compounds provide combinatorial benefit when used with approved chemotherapeutic and targeted agents. Through a large-scale in vitro combination screen, we show that CBP degrader treatment synergizes with multiple standard-of-care chemotherapies, including paclitaxel, as well as targeted agents, including CDK4/6 inhibitors. Furthermore, by genome-wide CRISPR knockout screening across four cell line models of different solid tumor types, we establish genetic determinants of resistance and sensitivity to CBP degradation in an EP300-mutant background, providing further mechanistic insight into combination therapy approaches. Collectively, we have defined cellular processes that present therapeutic vulnerabilities that can be leveraged for rational combination strategies with selective CBP degraders in solid tumor indications. Citation Format: Molly M. Wilson, Hafiz Ahmad, Benjamin Adams, Ketaki Adhikari, Wesley Austin, Breanna Bullock, Mike Collins, Danette Daniels, Julie Di Bernardo, Thomas Dixon, Claudia Dominici, Brian Ethell, Anais Gervais, Md Imran Hossain, Dave Lahr, Laura La Bonte, Michael Lehrke, Mei Yun Lin, David Mayhew, Karolina Mizeracka, Paige Monsen, Solymar Negretti, John Pulice, Abira Ramakrishnan, Darshan Sappal, Shawn Schiller, Samantha Schultz, Gromek Smolen, Nihan Ucisik, Grace Werosta, Elizabeth Wittenborn, Xiaohuan Wu, Qianhe Zhou, Mark Zimmerman. Establishing rational combination strategies with selective CBP degraders in solid tumor indications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1643.