Abstract 44: Synergistic antitumor activity of olaparib combined with AZD1775 in head and neck squamous cell carcinoma

Abstract

Abstract Purpose: Although the treatment of locally advanced head and neck cancer (HNSCC) has evolved in recent years, the cure rate for patients with aggressive tumors and high-risk of failure remains poor due to resistance to standard chemoradiotherapy. Since TP53, the gene that encodes the protein p53, is by far the most commonly mutated gene found in HNSCC, and is in turn associated with treatment failure and poor survival outcomes. Although HPV+ HNSCC has a good prognosis, a group of HPV+ patients' tumors remain refractory to conventional treatments and unusual patterns of recurrence and metastasis are emerging. Therefore, more effective therapies are urgently needed. Our recent work has demonstrated that increased DNA damage response associated induction of replication stress and impaired Rad51-mediated homologous recombination (HR) sensitizes HNSCC tumor cells to WEE1 kinase inhibition with AZD1775. While the use of single molecularly targeted agents has demonstrated limited therapeutic benefits, there is growing interest in targeting multiple pathways or multiple steps within a single pathway to achieve even more effective cancer treatments. In this context, combinations of agents that target the DNA damage and HR responses are an exciting new area of investigation. Given the synthetic lethality of PARP inhibitor, olaparib in BRCA1/2-mutant or HR repair-defective cancers, combining PARP inhibitors with agents that inhibit HR is another interesting area of intensive investigation. Therefore, we hypothesize that simultaneous targeting of PARP and WEE1 will decrease the clonogenic survival in vitro and inhibit tumor growth and prolong animal survival in treated mice in an in vivo orthotopic nude mouse model of oral cancer. Experimental Design: Clonogenic survival assays and an orthotopic mouse model of oral cancer were used to examine the in vitro and in vivo sensitivity of high-risk mutant p53 and HPV+ HNSCC cell lines to olaparib in combination with AZD1775 respectively. Cell cycle analysis, DNA damage (γH2AX), HR, live cell imaging, and apoptosis were performed to dissect molecular mechanisms. Results: We found that olaparib synergized with AZD1775 in vitro to inhibit growth of HNSCC cells irrespective of p53 status or HPV positivity (median CI = 0.07-0.19). Mechanistically, these drugs interact synergistically to induce DNA damage, replication stress, and impaired Rad51-mediated HR through activation of CDK1 and increased Chk1 phosphorylation preceded by enhanced activity of ATR, culminating in aberrant mitosis associated with apoptotic cell death. Assessment of olaparib and AZD1775 combination therapy in vivo in an orthotopic mouse model of oral cancer is currently underway. Conclusions: Olaparib synergizes with AZD1775 in HNSCC cells in vitro through apoptosis. Our data provide an early-preclinical evidence for the rational combination of WEE1 and PARP inhibitors in the treatment of advanced HNSCC. Citation Format: Hideaki Takahashi, Antje Lindemann, Ameeta A. Patel, Weiwei Liu, Noriaki Tanaka, Lin Tang, Mei Zhao, Walter N. Hittelman, Jeffrey N. Myers, Abdullah A. Osman. Synergistic antitumor activity of olaparib combined with AZD1775 in head and neck squamous cell carcinoma [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 44.