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

EP300 and CBP are paralogous, commonly expressed, master epigenetic enzymes, whose activity controls normal and malignant transcription. Here, we perform a cancer-wide, integrative chemical-genetic analysis, identifying that most cancer lineages, including osteosarcoma (OS), a highly lethal malignancy of bone, have relatively 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 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.