Abstract 58: Therapeutically targeting the cell cycle in head and neck cancer

Abstract

Abstract Head and neck squamous cell carcinomas (HNSCC) have a complex mutational spectrum with tumor suppressor and cell cycle dysregulation as the most prominent features. Additionally, HPV infection has been shown to be a cause of some HNSCC, particularly oropharyngeal cancer, and it is increasing in the US. Our recent studies have established WEE1 inhibition as a new therapeutic strategy in HNSCC. WEE1 inhibition not only leads to premature mitosis by weakening the G2/M checkpoint but also causes replication stress in S-phase particularly in tumors with deficient TP53. Given that HPV infection causes genetic instability by inactivating tumor suppressor pathways (TP53 and Rb) and impairing proper DNA damage repair (DDR) response, we aim to explore targets that will synergize with WEE1 and decrease reliance on chemotherapy. To this end, we performed a q-PCR array profiling p53 dependent gene expression in a pair of isogenic HNSCC cell lines for p53 knockdown (vs wildtype control). Using a similar profiling technique in an isogenic pair of immortalized human oral keratinocytes (OKF4 cells) over expressing HPV16 E6/E7 proteins, we profiled the expression of DDR genes in response to DNA damage in wildtype vs. E6E7 expressing keratinocytes. A functional high-throughput siRNA library screen for DDR genes was performed to functionally validate the pathways identified. We looked for DDR genes that specifically sensitized p53 deficient HNSCC cells as well as E6/E7 expressing cells to WEE1 inhibition. TP53 deficient cells exhibited elevated levels of DDR related genes in response to DNA damage when compared to isogenic wildtype. We identified potential survival DDR pathways for E6E7- mediated transformation, targeting of which represents a novel therapeutic strategy. The DDR siRNA screen with WEE1 inhibition provided a functional validation for our findings. Gene ontology analysis of top 10% of WEE1 sensitizers identified BRCA1 related DNA damage response genes as top sensitizers for WEE1 inhibition in p53 deficient cells. Collectively, these results would help develop a new therapeutic paradigm for HPV-positive HNSCC by providing tailored mechanism-based therapies. Citation Format: Ahmed Diab, Xu Chang, Michael Kao, Bruce Clurman, Denise Galloway, Mendez Eduardo. Therapeutically targeting the cell cycle in head and neck cancer [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 58.