Abstract 1503: Augmenting genomic instability in HPV head and neck cancer tumors through combination bromodomain and extra-terminal (BET) proteins inhibition and radiation treatments

Abstract

Abstract Integration of human papillomavirus (HPV)16 genomes into host head and neck squamous cell carcinoma (HNSCC) DNA is an essential driver for cancer progression. Currently, there are no treatment strategies based on HPV integration status. We postulate that a conceptual advance in the treatment of HPV HNSCC cancer can be formalized by targeting transcriptional co-regulator - bromodomain and extra-terminal (BET) proteins which mediate viral and host transcription. HPV maintenance in the host environment is dependent on BET protein-BRD4. An additional function of BET proteins in regulating transcription of tumor suppressors and DNA damage repair (DDR) genes. Given that patient populations have viral integrations into their genomes and its maintenance depends on cellular Brd4, displacing Brd4 through novel second-generation BET inhibitors can abrogate HPV transcription. Through chemical and knockdown studies of BET proteins in integrated viral HNSCC cells, we show viral oncogenes E6 and E7 are directly regulated by Brd4, reactivate tumor suppressors p53, release E2F1-Rb cell cycle brake to induce G1 cell cycle arrest, and significantly converge towards downregulation of DDR pathways in disrupted viral genomes. In contrast, non-disrupted viral genomes diverge from DDR pathways towards downregulation of interferon signaling pathways. As a result of the intrinsic genomic instability caused by the downregulation of components of the DDR machinery, the addition of external beam radiation further delayed DNA repair kinetics quantified through H2AX foci formation in cells harboring disrupted viral genomes. Taken together, targeting BET proteins is not a viable monotherapy but creates genomic instability, which, when combined with radiation, has the potential to eradicate HPV-associated tumors. Citation Format: Aakarsha Rao, Zijian Ni, Albert Wang, Dhruthi Suresh, Chitrasen Mohanty, Christina Kendziorski, Gopal Iyer. Augmenting genomic instability in HPV head and neck cancer tumors through combination bromodomain and extra-terminal (BET) proteins inhibition and radiation treatments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1503.