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

By Manish kumar, David Molkentine, Jessica Molkentine, Kathleen Bridges, Tongxin Xie, Liang Yang, Andrew Hefner, Meng Gao, Mitchell J Frederick, Sahil Seth, Mohamed Abdelhakiem, Beth M. Beadle, Faye Johnson, Jing Wang, Li Shen, Timothy Heffernan, Aakash Sheth, Robert Ferris, Jeffrey N Myers, Curtis R Pickering, Heath D Skinner

Posted 11 Apr 2020
bioRxiv DOI: 10.1101/2020.04.10.028217

Despite radiation forming the curative backbone of over 50% of malignancies, there are no genomically-driven radiation sensitizers for clinical use. We performed in vivo shRNA screening to identify targets generally associated with radiation response as well as those exhibiting a genomic dependency. This identified 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 confirmed this phenomenon was due to repression of homologous recombination following DNA damage and can be reproduced 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 targets by HAT inhibition. Additionally, mutations in CREBBP/EP300 were associated with recurrence following radiation, in several squamous cell carcinoma cohorts. These findings represent both a novel mechanism of treatment resistance and the potential for genomically-driven treatment. ### Competing Interest Statement The authors have declared no competing interest.

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