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

ABSTRACT: Cancer cells are highly 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, 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. Mechanistically, combinations of AKT inhibitors and JQAD1 suppress the growth of AKT-dysregulated OS. These observations extend across >850 cancer cell lines, where these agents positively combine in a manner mechanistically dependent on control of protein synthesis. Finally, combination treatment is synergistic in 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE305936 | GEO | 2026/09/22

REPOSITORIES: GEO

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Project description:EP300 and CBP are paralogous, multidomain histone acetyltransferases (HATs) that regulate gene expression by binding to and acetylating diverse proteins. With widespread effects on gene regulation, these enzymes are attractive targets for therapeutic development. Discovery efforts for chemical inhibitors typically target protein domains that are amenable to probe binding. In some cases, probes have been identified for more than one domain within a single protein, including high potency inhibitors of both the catalytic HAT domain and bromodomain (BRD) that mediate the enzymatic and protein binding (“reader”) activities of EP300/CBP. In cancer cell systems, combination inhibition of both domains is more toxic than single inhibitor alone, indicating that inhibition of individual domain functions may elicit differential effects. Thus, we hypothesized that determining the relative effects of domain-specific inhibition of EP300/CBP on tumor cell growth may elucidate exceptional-responding tumor types to one inhibitor or the other. This would permit a broader therapeutic index by enabling reduced dosing of domain-targeted inhibitors, while maintaining enhanced inhibition of cancer cell growth. Here, using high-throughput cell line-based screening, we demonstrate that targeting the HAT or BRD domains of EP300/CBP using the chemical probes A485 and CCS1477 has differential effects in select tumor types. Group 3 medulloblastoma (G3MB) cells were especially sensitive to EP300/CBP BRD inhibition, as compared with HAT inhibition. Structurally, these effects are mediated by the difluorophenyl group in the catalytic core of CCS1477. Mechanistically, the effects of bromodomain and HAT-domain specific inhibition are distinct, with bromodomain inhibition causing rapid early disruption of genetic dependency networks that are required for G3MB growth. These studies provide a domain-specific structural foundation for drug discovery efforts targeting EP300/CBP and identify a selective role for the EP300/CBP bromodomain in maintaining genetic dependency networks in G3MB cells.

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

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