Abstract B043: Dysregulated AKT signaling reprograms osteosarcoma to drive selective reliance on EP300

Cancer cells are highly dependent on the control of transcription for maintenance of the malignant cell state. EP300 and CBP are paralogous, commonly expressed, master epigenetic enzymes, whose activity controls normal and malignant transcription. Here, we perform an integrative chemical-genetic cancer-wide analysis, identifying that most cancer lineages, including osteosarcoma (OS), a highly lethal malignancy of bone, have enhanced dependency on EP300, compared with CBP. To take advantage of selective pharmacology targeting EP300 alone, which spares CBP in untransformed cells and thereby reduces toxicity, we used the EP300-targeted degrader JQAD1. A specific genetic subgroup of OS marked by dysregulation of the PIK3CA-AKT-mTOR pathway is genetically dependent on EP300 and uniquely sensitive to EP300 degradation. Expression of constituitively active AKT in insensitive OS cells induces sensitivity to JQAD1, driven by physical relocalization of EP300, CBP and H3K27ac to genetic subtype-enriched dependency loci. Mechanistically, combinations of AKT inhibitors and JQAD1 suppress the growth of AKT-dysregulated OS in vitro and in orthotopic xenografts. These observations extend across >850 cancer cell lines, where these agents positively combine in a manner mechanistically dependent on control of protein synthesis. These findings reveal genetic and transcriptional determinants of EP300 degrader function in high-risk OS and provide a foundation for biomarker-directed investigation of co-targeting of EP300 and AKT for therapeutic gain across cancers marked by enhanced protein translation. Citation Format: Ian Delahunty, Stephanie Nance, Yang Zhang, Francois Lamoureux, Qi Liu, Charlie Wright, Noha Shendy, Sandra Kietlinska, Barbara De Kegel, Matthew Rees, Anoop Kavirayani, Paris Prinsen, Yousef Khashana, Melissa Ronan, Jennifer Roth, Alejandro Sweet-Cordero, Lilly Guenther, Paul Geeleher, Ben Ory, Jun Qi, Brian Abraham, Adam Durbin. Dysregulated AKT signaling reprograms osteosarcoma to drive selective reliance on EP300 [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery and Innovation in Pediatric Cancer— From Biology to Breakthrough Therapies; 2025 Sep 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_2): nr B043.