GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE331nnn/GSE331358/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE331358GEOGSEfalseDysregulated AKT signaling reprograms osteosarcoma to drive selective reliance on EP300 [RNA-seq II]Cancers are dependent on transcriptional control to maintain 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 the highly lethal malignancy of bone, osteosarcoma (OS). We use selective pharmacology targeting EP300 alone that spares CBP in untransformed cells and thereby reduces toxicity, to identify that a specific genetic subgroup of OS marked by dysregulation of the PI3K-AKT-mTOR pathway is 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. Combinations of AKT inhibitors and JQAD1 synergistically 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 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 co-targeting EP300 and AKT across cancers marked by enhanced protein translation.2026/09/22GSE331358GSM9744604GSM9744603GSM9744608GSM9744607GSM9744606GSM974460534284331358Homo sapiens