Inhibition of histone acetyltransferase function radiosensitizes CREBBP/EP300 mutants via repression of homologous recombination, potentially targeting a gain of function

Manish Kumar, David Molkentine, Jessica Molkentine, Kathleen Bridges, Tongxin Xie, Liangpeng Yang, Andrew Hefner, Meng Gao, Reshub Bahri, Annika Dhawan, Mitchell J. Frederick, Sahil Seth, Mohamed Abdelhakiem, Beth M. Beadle, Faye Johnson, Jing Wang, Li Shen, Timothy Heffernan, Aakash Sheth, Robert L. Ferris, Jeffrey N. Myers, Curtis R. Pickering and Heath D. Skinner ()
Additional contact information
Manish Kumar: All India Institute of Medical Sciences (AIIMS)
David Molkentine: University of Pittsburgh, UPMC Hillman Cancer Center
Jessica Molkentine: University of Pittsburgh, UPMC Hillman Cancer Center
Kathleen Bridges: University of Texas, MD Anderson Cancer Center
Tongxin Xie: University of Texas, MD Anderson Cancer Center
Liangpeng Yang: University of Texas, MD Anderson Cancer Center
Andrew Hefner: University of Pittsburgh, UPMC Hillman Cancer Center
Meng Gao: University of Texas, MD Anderson Cancer Center
Reshub Bahri: University of Pittsburgh, UPMC Hillman Cancer Center
Annika Dhawan: University of Pittsburgh, UPMC Hillman Cancer Center
Mitchell J. Frederick: Baylor College of Medicine
Sahil Seth: University of Texas, MD Anderson Cancer Center
Mohamed Abdelhakiem: University of Pittsburgh, UPMC Hillman Cancer Center
Beth M. Beadle: Stanford University
Faye Johnson: University of Texas, MD Anderson Cancer Center
Jing Wang: The University of Texas Graduate School of Biomedical Sciences
Li Shen: University of Texas, MD Anderson Cancer Center
Timothy Heffernan: University of Texas, MD Anderson Cancer Center
Aakash Sheth: Baylor College of Medicine
Robert L. Ferris: University of Pittsburgh, UPMC Hillman Cancer Center
Jeffrey N. Myers: University of Texas, MD Anderson Cancer Center
Curtis R. Pickering: University of Texas, MD Anderson Cancer Center
Heath D. Skinner: University of Pittsburgh, UPMC Hillman Cancer Center

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract Despite radiation forming the curative backbone of over 50% of malignancies, there are no genomically-driven radiosensitizers for clinical use. Herein we perform in vivo shRNA screening to identify targets generally associated with radiation response as well as those exhibiting a genomic dependency. This identifies the histone acetyltransferases CREBBP/EP300 as a target for radiosensitization in combination with radiation in cognate mutant tumors. Further in vitro and in vivo studies confirm this phenomenon to be due to repression of homologous recombination following DNA damage and reproducible using chemical inhibition of histone acetyltransferase (HAT), but not bromodomain function. Selected mutations in CREBBP lead to a hyperacetylated state that increases CBP and BRCA1 acetylation, representing a gain of function targeted by HAT inhibition. Additionally, mutations in CREBBP/EP300 are associated with recurrence following radiation in squamous cell carcinoma cohorts. These findings provide both a mechanism of resistance and the potential for genomically-driven treatment.

Date: 2021
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DOI: 10.1038/s41467-021-26570-8

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