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CREBBP/EP300 mutation is associated with poor outcome in HNSCC and targetable with synthetic cytotoxicity.

By Manish Kumar, David Molkentine, Jessica Molkentine, Kathleen Bridges, Tongxin Xie, Liangpeng Yang, Meng Gao, Mitchell J Frederick, Sahil Seth, Mohamed Abdelhakiem, 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

Background: Head and neck squamous cell carcinoma (HNSCC) harbors few directly targetable mutations, however several mutations in this malignancy may be sensitive to synthetic cytotoxicity. Methods: Whole exome sequencing in human HNSCC tumors (n=235) was analyzed for effect on outcome. In vivo shRNA screening in HNSCC models was performed following by in vitro and in vivo studies of tumor response and DNA damage repair. Results: Mutation in either the histone acetyltransferases CREBBP and EP300 or CASP8 were associated with poor outcome following radiation therapy in HNSCC. In vivo shRNA screening identified synthetic cytotoxicity in CREBBP/EP300 mutant tumors by combining radiation and inhibition of histone acetyltransferase (HAT) function. This effect appears to be due to increased DNA damage following ionizing radiation through inhibition of homologous recombination and altered acetylation of histone marks. Conclusion: CREBBP/EP300 mutation is associated with radiation resistance in HNSCC and is targetable via synthetic cytotoxicity. ### Competing Interest Statement The authors have declared no competing interest.

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