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Group 3 medulloblastoma transcriptional networks collapse under domain specific EP300/CBP inhibition

Author

Listed:
  • Noha A. M. Shendy

    (St. Jude Children’s Research Hospital)

  • Melissa Bikowitz

    (Moffitt Cancer Center
    University of South Florida)

  • Logan H. Sigua

    (Dana-Farber Cancer Institute)

  • Yang Zhang

    (St. Jude Children’s Research Hospital)

  • Audrey Mercier

    (St. Jude Children’s Research Hospital)

  • Yousef Khashana

    (St. Jude Children’s Research Hospital)

  • Stephanie Nance

    (St. Jude Children’s Research Hospital)

  • Qi Liu

    (Dana-Farber Cancer Institute)

  • Ian M. Delahunty

    (St. Jude Children’s Research Hospital)

  • Sarah Robinson

    (St. Jude Children’s Research Hospital)

  • Vanshita Goel

    (St. Jude Children’s Research Hospital)

  • Matthew G. Rees

    (The Broad Institute of MIT and Harvard)

  • Melissa A. Ronan

    (The Broad Institute of MIT and Harvard)

  • Tingjian Wang

    (Dana-Farber Cancer Institute)

  • Mustafa Kocak

    (The Broad Institute of MIT and Harvard)

  • Jennifer A. Roth

    (The Broad Institute of MIT and Harvard)

  • Yingzhe Wang

    (St Jude Children’s Research Hospital)

  • Burgess B. Freeman

    (St Jude Children’s Research Hospital)

  • Brent A. Orr

    (St Jude Children’s Research Hospital)

  • Brian J. Abraham

    (St. Jude Children’s Research Hospital)

  • Martine F. Roussel

    (St. Jude Children’s Research Hospital)

  • Ernst Schonbrunn

    (Moffitt Cancer Center
    University of South Florida)

  • Jun Qi

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Adam D. Durbin

    (St. Jude Children’s Research Hospital)

Abstract

Chemical discovery efforts commonly target individual protein domains. Many proteins, including the EP300/CBP histone acetyltransferases (HATs), contain several targetable domains. EP300/CBP are critical gene-regulatory targets in cancer, with existing high potency inhibitors of either the catalytic HAT domain or protein-binding bromodomain (BRD). A domain-specific inhibitory approach to multidomain-containing proteins may identify exceptional-responding tumor types, thereby expanding a therapeutic index. Here, we discover that targeting EP300/CBP using the domain-specific inhibitors, A485 (HAT) or CCS1477 (BRD) have different effects in select tumor types. Group 3 medulloblastoma (G3MB) cells are especially sensitive to BRD, compared with HAT inhibition. Structurally, these effects are mediated by the difluorophenyl group in the catalytic core of CCS1477. Mechanistically, bromodomain inhibition causes rapid 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.

Suggested Citation

  • Noha A. M. Shendy & Melissa Bikowitz & Logan H. Sigua & Yang Zhang & Audrey Mercier & Yousef Khashana & Stephanie Nance & Qi Liu & Ian M. Delahunty & Sarah Robinson & Vanshita Goel & Matthew G. Rees &, 2024. "Group 3 medulloblastoma transcriptional networks collapse under domain specific EP300/CBP inhibition," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47102-0
    DOI: 10.1038/s41467-024-47102-0
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