Abstract 2925: Targeting histone acetyltransferase (HAT) function for synthetic cytotoxicity in CREBBP/EP300 mutant tumors

CREB-binding protein (CREBBP) and E1A binding protein p300 (EP300) share significant homology and are collectively mutated in ~14% of head and neck cancers (HNSCC). Recently we have identified CREBBP/EP300 mutations being associated with poor outcome. Thus, tumors which harbor these mutations may be an ideal subset to study for agents that lead to synthetic cytotoxicity. We have performed in vivo shRNA screening combined with radiation in tumors derived from human HNSCC cell lines (CREBBP/EP300 mutant: Cal27, UMSCC22A, UMSCC47; CREBBP/EP300 wild type: UPCISCC152, HN31) to identify targets that are synthetically cytotoxic when combined with radiation in the CREBBP/EP300 mutant background. This identified CREBBP and EP300 proteins as the most significant targets. Additionally, inhibition of either CREBBP or EP300 with shRNA, combined with radiation, led to increased γ-H2AX, decreased BRCA1, increased apoptosis and increased cell death in CREBBP/EP300 mutant, but not wild type cells. In vivo studies of CREBBP mutant tumors using both HPV (+) and HPV (-) xenograft models showed dramatically increased tumor growth delay (TGD) following radiation in CREBBP knockdown tumors, but not controls, with 40-80% of tumors cured after low doses of XRT. This was accompanied by increased TUNEL staining in shCREBBP tumors following radiation (p Citation Format: Curtis Pickering, Manish Kumar, Kathleen Bridges, Tongxin Xie, David Molkentine, Aakash Sheth, Liang Yang, Mitchell Frederick, Tim Heffernan, Sahil Seth, Jeffrey Myers, Heath D. Skinner. Targeting histone acetyltransferase (HAT) function for synthetic cytotoxicity in CREBBP/EP300 mutant tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2925.