Abstract 70: PARP1 as a potential therapeutic target in Merkel cell carcinoma

Abstract

Abstract Background: Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin tumor. Patients with incurable disease are treated with the same chemotherapy agents utilized in small-cell lung cancer (SCLC) achieving similar responses. Overexpression of PARP1 is common in SCLC and promising antitumor activity of PARP inhibitors is being demonstrated in early clinical trials. Furthermore, PARP inhibitors are active in a subset of tumors harboring mutations in DNA-damage repair (DDR) genes and benefit correlates to response to platinum. Based on its similarities with SCLC, its association with DNA damage by UV light, and its sensitivity to platin, our study explores PARP1 as a therapeutic target in MCC. Methods: We evaluated the prevalence of PARP1 expression by immunohistochemistry in 19 MCC. Polyoma virus (MCPyV) status was evaluated by staining with anti-MCPyV antibody in the tissue specimens. Exome-sequencing of 263 genes was performed in 14 patients' samples using next-generation sequencing. Only mutations predicted to impair protein function in 17 genes related to DDR or mismatch repair were included in our analysis. Fisher's exact test was used for statistical significance. Results: The majority of MCC express PARP1 (84%), suggesting underlying defects in DNA damage repair. Approximately half of the tumors (47%) were associated with MCPyV. There was no statistical correlation between PARP1 expression and MCPyV status or primary site of disease. Mutations in genes predicted to impair DDR was identified in 9 samples (64%), occurred exclusively in head and neck primaries, and correlated with mutations in TP53 or RB1 (P=0.03). Mutations in ARID1A predictive to be loss-of-function and potentially confer sensitivity to PARP inhibitors were found in 36% of the patients, exclusively in MCPyV negative samples (P=0.003). Mutations in TP53 and/or RB1 were more frequent in MCPyV negative tumors (P=0.03). Conclusions: In spite of the small sample size, the high prevalence of PARP1 expression in MCC samples, similarly to SCLC, suggests that patients with MCC might also benefit from PARP1 inhibitors. Furthermore, the frequent mutations in genes involved in DNA-damage repair and ARID1A, particularly in the MCPyV negative cases, merits further characterization. Taken together, we believe clinical trials with PARP inhibitors in MCC patients should be considered. Citation Format: Renata Ferrarotto, Shirley Su, Lixia Diao, A Karina Eterovic, Victor Prieto, William Morrison, Jing Wang, Bonnie Glisson, Merrill Kies, Diana Bell. PARP1 as a potential therapeutic target in Merkel 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 70.