Abstract 3111: Synthetic lethality in head and neck cancer

Abstract

Abstract Current treatment for advanced stage head and neck squamous cell carcinoma (HNSCC) typically include both radiation and chemotherapy, which is associated with significant morbidity. Our main objective was to explore a novel adjuvant molecular therapy approach to minimize the chemoradiation-induced side effects and toxicities, while maintaining therapeutic anti-tumor effects in HNSCC through the mechanism of synthetic lethality that has been already exploited to a limited extent in clinical trials for breast cancer. It has been demonstrated that synthetic lethality is based on the roles of Poly(ADP-ribose)polymerase-1 (PARP-1) in DNA single-stranded break (SSB) repair, and BRCA-1 and -2 in double-stranded break (DSB) repair. By simply inhibiting PARP-1 in tumor cells carrying a mutation in the Brca genes, one would expect complete tumor regression. The MRN complex (Mre11, Rad50, and Nbs-1) is well recognized as a key sensor of DSBs and acts by recruiting and activating DNA damage response proteins. These concepts led us to investigate the concept of introducing a mutation to the MRN complex, in combination with PARP-1 inhibition, thereby creating “dual hits” that would result in synthetic lethality within tumors expressing wild-type Brca genes such as HNSCC. Human HNSCC tumor cell lines and a mouse model with human HNSCC were used in the study. Wild-type MRN and PARP expressions were detected in these tumor cells. In vitro and in vivo studies were performed to evaluate synthetic lethality effects after combining PARP-1 inhibition with adenovirus-mediated Nbs-1 (Ad-Nbs-1) gene transfer treatment, which we had previously shown to impair MRN expression. Telomere length was measured to investigate the potential mechanism of synthetic lethality. Our study demonstrates that significant synthetic lethality was found with combined PARP-1 inhibition and Ad-Nbs-1 treatment in both in vitro and in vivo experiments; it also suggests that the telomere maintenance may play an important role in synthetic lethality. In conclusion, we propose an important novel mechanism responsible for the synthetic lethality of PARP-1 inhibitors and MRN disruption based on their roles on telomere maintenance. Our findings emphasize the potential benefits of our therapeutic approach and deserve further investigation to help obviate the toxicities associated with existing treatment regimens for HNSCC patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3111. doi:1538-7445.AM2012-3111