Abstract Cancer cells are 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, using a cancer-wide integrative chemical-genetic analysis, we find enhanced dependency on EP300 compared to CBP in most cancer lineages, including osteosarcoma (OS). OS is a highly lethal malignancy of bone and has enhanced dependency on EP300, compared with CBP. To take advantage of selective pharmacology targeting EP300 alone that spares CBP in untransformed cells and thereby reduces toxicity, we used the EP300-targeted degrader JQAD1. We identify a specific genetic subgroup of OS, marked by dysregulation of the PI3K-AKT-mTOR pathway, that is both genetically dependent on EP300 and uniquely sensitive to EP300 degradation. Expression of constitutively 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. These observations extend across 850 cancer cell lines, where multiple AKT inhibitors, including the FDA-approved capivasertib, positively combine with EP300 degraders in a manner mechanistically dependent on control of protein synthesis. Finally, combination treatment is synergistic in AKT-dysregulated, orthotopic OS xenografts. 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, W. Charlie Wright, K. Elaine Ritter, Noha A. Shendy, Benedicte Brounais, Sandra Kietlinska, Barbara De Kegel, Matthew G. Rees, Mustafa Kocak, Ashish B. George, Anoop M. Kavirayani, Paris P. Prinsen, Yousef Khashana, Melissa M. Ronan, Jennifer Roth, Alejandro Sweet-Cordero, Xiaotu Ma, Lillian M. Guenther, Paul Geeleher, Benjamin Ory, Jun Qi, Brian Abraham, Adam D. Durbin. Dysregulated AKT signaling reprograms osteosarcoma to drive selective reliance on EP300 abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4024.
Delahunty et al. (Fri,) studied this question.