Dysregulated AKT signaling reprograms osteosarcoma to drive selective reliance on EP300
8 affiliations
- 1Division of Molecular Oncology, Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
- 2Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
- 3Nantes Université , INSERM UMR 1307, CNRS UMR 6075, CRCI2NA, Nantes, France.
- 4Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA, USA.
- 5St. Jude Graduate School of Biomedical Sciences, St. Jude Children's Research Hospital , Memphis, TN, USA.
- 6Broad Institute of MIT and Harvard , Cambridge, MA, USA.
- 7Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
- 8Division of Pediatric Oncology, Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.
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.
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BibTeX
@article{delahunty2026dysregulated,
title = {{Dysregulated AKT signaling reprograms osteosarcoma to drive selective reliance on EP300}},
author = {Ian M Delahunty and Stephanie Nance and Yang Zhang and Francois Lamoureux and Qi Liu and William C Wright and K Elaine Ritter and Noha A M Shendy and Bénédicte Brounais-Le Roye and Sandra J Kietlinska and Mohammad A Mohammad Nezhady and Yuan Feng and Barbara De Kegel and Matthew G Rees and Mustafa Kocak and Ashish B George and Meifen Lu and Anoop M Kavirayani and Bo Wang and Yanling Liu and Paris E A Prinsen and Yousef Khashana and Vernon Justice Ebegboni and Melissa M Ronan and Jennifer A Roth and E Alejandro Sweet-Cordero and Lillian M Guenther and Paul Geeleher and Xiaotu Ma and Benjamin Ory and Jun Qi and Brian J Abraham and Adam D Durbin},
journal = {Journal of Experimental Medicine},
year = {2026},
month = oct,
doi = {10.1084/jem.20251898},
url = {https://hal.science/hal-05829036v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Dysregulated AKT signaling reprograms osteosarcoma to drive selective reliance on EP300
AU - Ian M Delahunty
AU - Stephanie Nance
AU - Yang Zhang
AU - Francois Lamoureux
AU - Qi Liu
AU - William C Wright
AU - K Elaine Ritter
AU - Noha A M Shendy
AU - Bénédicte Brounais-Le Roye
AU - Sandra J Kietlinska
AU - Mohammad A Mohammad Nezhady
AU - Yuan Feng
AU - Barbara De Kegel
AU - Matthew G Rees
AU - Mustafa Kocak
AU - Ashish B George
AU - Meifen Lu
AU - Anoop M Kavirayani
AU - Bo Wang
AU - Yanling Liu
AU - Paris E A Prinsen
AU - Yousef Khashana
AU - Vernon Justice Ebegboni
AU - Melissa M Ronan
AU - Jennifer A Roth
AU - E Alejandro Sweet-Cordero
AU - Lillian M Guenther
AU - Paul Geeleher
AU - Xiaotu Ma
AU - Benjamin Ory
AU - Jun Qi
AU - Brian J Abraham
AU - Adam D Durbin
PY - 2026
DA - 2026/10/20
JO - Journal of Experimental Medicine
DO - 10.1084/jem.20251898
UR - https://hal.science/hal-05829036v1
AB - 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.
SN - 0022-1007
SN - 1540-9538
ER -