Abstract 5814: Synthetic lethal therapy to overcome resistance to AURKA inhibition in HPV-negative head and neck cancer

Abstract

Abstract Head and neck squamous cell carcinomas (HNSCC) affect more than a half million people annually worldwide. Most currently available treatments, which include cisplatin and irradiation, are associated with significant morbidity, while many targeted inhibitors show limited single agent efficacy: novel therapeutic approaches which combine efficacy and limited toxicity are needed. The most common mutational event in human papillomavirus (HPV)-negative HNSCC is mutation of TP53. As control of the G1/S transition is entirely p53-dependent, cells with TP53 mutations lose the G1/S checkpoint, and evade radiation- and cisplatin-induced cellular senescence. Targeting the serine/threonine mitotic kinase Aurora-A (AURKA) emerged as a promising synthetic lethal approach in this setting. AURKA is negatively regulated by p53, which causes upregulation of AURKA in the majority of cases of HNSCC, correlating with poor prognosis and cisplatin resistance. The single agent AURKA inhibitor MLN8237 (alisertib) had a 9% monotherapy response rate in treatment-refractory HNSCC, with all responses occurring in HPV-negative or -unknown disease. In our study, we used initial high throughput screening in multiple genomically characterized HNSCC cell lines to identify synergistic combinations involving AURKA inhibitors and 20 other inhibitors of cell cycle, and cell cycle checkpoint controls. This work has identified has several effective combinations, particularly in between alisertib (targeting AURKA), danusertib (AURKA and AURKB), LY2606368/prexasertib (CHK1), and reversine (MPS1). Multiplexing analysis with measures of cell metabolism, direct visualization of mitotic nuclei, and additional assays has allowed us to dissect distinct execution points for different drug combinations. We will describe in detail mechanistic interactions between specific combinations of value for HNSCC. These drug combinations are likely to represent a new and effective modality for treating TP53-mutated cancers. Citation Format: Alexander Y. Deneka, Margret B. Einarson, Jong Woo Lee, Anna S. Nikonova, Barbara Burtness, Erica A. Golemis. Synthetic lethal therapy to overcome resistance to AURKA inhibition in HPV-negative head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5814.