Abstract
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.
Footnotes
The authors report no conflict of interest related to this manuscript.