Dysregulated AKT signaling reprograms osteosarcoma to drive selective reliance on EP300 [RNA-seq II]

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.