Dysregulated AKT signaling reprograms osteosarcoma to drive selective reliance on EP300

Cancers depend on transcriptional control to maintain the malignant cell state. EP300 and CBP are paralogous master epigenetic enzymes that control normal and malignant transcription. Using a cancer-wide integrative chemical-genetic analysis, we demonstrate enhanced dependency on EP300, compared with CBP, in cell lines from most cancer lineages, including lethal osteosarcoma (OS). Using a selective EP300 degrader (JQAD1), we identify that a genetically defined subgroup of OS with dysregulation of the PI3K–AKT–mTOR pathway is genetically and chemically sensitive to loss of EP300. Activated AKT promotes sensitivity to JQAD1, driven by relocalization of EP300, CBP and H3K27ac to genetic subtype-enriched dependency loci. AKT inhibition combines with JQAD1 to synergistically suppress the growth of AKT-dysregulated OS cells in vitro and in orthotopic xenografts. These observations extend across >850 cancer cell lines, where synergy is predicted by elevated protein synthetic rates. These findings reveal determinants of EP300 degrader function in OS and provide a foundation for co-targeting EP300 and AKT in cancers with enhanced protein translation.