Abstract 604: Combination of the Aurora A inhibitor TAS-119 and adavosertib results in synergistic c-Jun-mediated cell death in head and neck and lung cancers

Abstract

Abstract Head and neck squamous cell carcinomas (HNSCC) account for more than 800,000 cases annually worldwide. Human papillomavirus (HPV)-negative HNSCC mainly harbor disruptive mutations in TP53 and/or CDKN2A tumor suppressor genes, which are associated with refractoriness to treatment as well as poor prognosis and survival. Synthetic lethal approaches hold promise for such patients. Cancers with TP53/CDKN2A mutations lose the G1/S checkpoint, and foster a dependence on the G2/M checkpoint as the primary mechanism to repair the resulting accumulation of genomic instability, thus creating a vulnerability that can potentially be exploited with synthetic lethal targeted therapy. We have previously demonstrated in HPV-negative HNSCC patients that elevation in expression of Aurora kinase A (AURKA), a crucial mitotic regulator, is correlated with worse outcome. Combined inhibition of AURKA and WEE1, a G2/M checkpoint kinase, resulted in a synergistic anti-tumor effect in HNSCC in vitro and in vivo. Upon these findings, we confirmed synergy in testing the more specific AURKA inhibitor, TAS-119 in HNSCC and lung cancers harboring TP53 mutations, and explored mechanisms of cell death. TAS119 and adavosertib combination treatment synergistically suppressed cell viability, clonogenic cell survival, anchorage-independent cell growth in soft agar and oncosphere formation relative to vehicle and single-agent treatment in HNSCC FaDu and CAL27 cells, and lung cancer NCI-H520 and NCI-H358 cells bearing TP53/CDKN2A mutations. Of note, this synergistic anti-tumor effect was not seen in normal human tracheobronchial epithelial cells, predicting a favorable therapeutic index. Furthermore, combination treatment accelerated an accumulation of mitotic catastrophe with mitotic arrest, and led to apoptotic cell death. Mechanistically, combination TAS-119 and adavosertib in HNSCC cells drastically augmented DNA damage and phosphorylation of c-Jun (Ser 63) as demonstrated by kinase array and western blotting, indicating an activation of c-Jun-mediated pro-apoptotic genes. In vivo, this combination demonstrated a synergistic suppressive effect on tumor growth in FaDu xenografts compared with either vehicle or single-agent treatment. Taken together, these results support the promise of further clinical evaluation of AURKA inhibitor in combination with WEE1 inhibitor as a novel and effective treatment for HNSCC and lung cancer patients with TP53/CDKN2A mutations. Citation Format: Jong Woo Lee, Cindy Yang, Barbara Burtness. Combination of the Aurora A inhibitor TAS-119 and adavosertib results in synergistic c-Jun-mediated cell death in head and neck and lung cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 604.