Cancer Therapy : Preclinical Dual Disruption of DNA Repair and Telomere Maintenance for the Treatment of Head and Neck Cancer

Purpose: Poly(ADP-ribose) polymerases (PARP) and the Mre11, Rad50, and Nbs1 (MRN) complex are key regulators of DNA repair, and have been recently shown to independently regulate telomere length. Sensitivity of cancers to PARPi is largely dependent on the BRCAness of the cells. Unfortunately, the vast majority of cancers are BRCA-proficient. In this study, therefore, we investigated whether a targeted molecular "hit" on theMRN complex, which is upstream of BRCA, can effectively sensitize BRCA-proficient head and neck squamous cell carcinoma (HNSCC) to PARP inhibitor (PARPi). Experimental Design:HumanHNSCC cell lines and amousemodel with HNSCC xenografts were used in this study. In vitro and in vivo studieswere conducted to evaluate the effects andunderlyingmechanisms of dual molecular disruption of PARP and the MRN complex, using a pharmacologic inhibitor and a dominant-negative Nbs1 expression vector, respectively. Results: Our findings demonstrate that downregulation of the MRN complex disrupts homologous recombination, and, when combined with PARPi, leads to accumulation of lethal DNA double-strand breaks. Moreover, we show that PARPi and MRN complex disruption induces significantly shortening telomere length. Together, our results demonstrate that dual disruption of these pathways causes significant cell death in BRCA-proficient tumor cells both in vitro and in vivo. Conclusion: Our study, for the first time, elucidates a novel mechanism for MRN complex and PARP inhibition beyondDNA repair, demonstrating the feasibility of a dual disruption approach that extends the utility of PARPi to the treatment of BRCA-proficient cancers. Clin Cancer Res; 1–14. 2014 AACR.