Year: 2026
Type: article
Abstract: Cancers depend on transcriptional control to maintain the malignant cell state. EP300 and CBP are paralogous master epigenetic enzymes that control normal and malignant transcription. Using a cancer-wide integrative chemical-genetic analysis, we demonstrate enhanced dependency on EP300, compared with CBP, in cell lines from most cancer lineages, including lethal osteosarcoma (OS). Using a selective EP300 degrader (JQAD1), we identify that a genetically defined subgroup of OS with dysregulation of the PI3K-AKT-mTOR pathway is genetically and chemically sensitive to loss of EP300. Activated AKT promotes sensitivity to JQAD1, driven by relocalization of EP300, CBP and H3K27ac to genetic subtype-enriched dependency loci. AKT inhibition combines with JQAD1 to synergistically suppress the growth of AKT-dysregulated OS cells in vitro and in orthotopic xenografts. These observations extend across >850 cancer cell lines, where synergy is predicted by elevated protein synthetic rates. These findings reveal determinants of EP300 degrader function in OS and provide a foundation for co-targeting EP300 and AKT in cancers with enhanced protein translation.
DOI: 10.1084/jem.20251898
Authors: Ian M. Delahunty, Stephanie Nance, Yang Zhang, Francois Lamoureux, Qi Liu, William C. Wright, K. Elaine Ritter, Noha A.M. Shendy, Bénédicte Brounais-Le Roye, Sandra J. Kietlinska, Mohammad A. Mohammad Nezhady, Yuan Feng, Barbara De Kegel, Matthew G. Rees, Mustafa Kocak, Ashish B. George, Meifen Lu, Anoop M. Kavirayani, Bo Wang, Yanling Liu, Paris E.A. Prinsen, Yousef Khashana, Vernon Justice Ebegboni, Melissa M. Ronan, Jennifer A. Roth, E. Alejandro Sweet-Cordero, Lillian M. Guenther, Paul Geeleher, Xiaotu Ma, Benjamin Ory, Jun Qi, Brian J. Abraham, Adam D. Durbin
Institutions: St. Jude Children's Research Hospital, Centre National de la Recherche Scientifique, Inserm, Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes Angers, Nantes Université, Harvard University, Dana-Farber Cancer Institute, Broad Institute, University of California, San Francisco
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Funders: American Association for Cancer Research, V Foundation for Cancer Research, Alex's Lemonade Stand Foundation for Childhood Cancer, Rally Foundation, CureSearch for Children's Cancer, St. Jude Children's Research Hospital, Dana-Farber Cancer Institute, American Lebanese Syrian Associated Charities, Broad Institute, Curing Kids Cancer, Ligue Contre le Cancer, National Institutes of Health, National Cancer Institute, Hyundai Hope On Wheels
Awards: Targeting EP300, a selective dependency in neuroblastoma, G2954099590, G4869702982, G9000342606, Dissecting high-risk cell states in neuroblastoma, Reprogramming myogenic regulatory factors in RMS to promote differentiation and halt growth, Cancer Center Support Grant (CCSG), Targeting EP300 epigenomic control in neuroblastoma
OpenAlex ID: W7223011806