Abstract 3748: The Mre11/Rad50/Nbs1 (MRN) complex: A critical mediator of chemoresistance and cancer stem cell progression in head and neck squamous cell carcinoma.

Abstract While platinum-based agents like cisplatin (DDP) are the mainstay of chemotherapeutic options for several tumor types, including ovarian, lung, and head and neck squamous cell carcinoma, resistance to these agents can significantly contribute to treatment failure and increase the need for higher toxic doses. Tumors are heterogeneous in nature, with their growth sustained by a small subpopulation of highly malignant cells, termed cancer stem cells (CSCs). These cells comprise the top of the tumor cell hierarchy, are remarkably chemoresistant, and are associated with tumor recurrence. Enhanced repair of DNA double stand breaks (DSBs) may compensate for DDP induced damage and contribute to chemoresistance in tumor cells. The Mre11/Rad50/Nbs1 (MRN) complex is a key player in DNA DSB repair, telomere maintenance, and cell cycle checkpoint control, and has been associated with DDP resistance. The present study investigates the role of MRN in the development of a CSC-mediated chemoresistant phenotype and its associated molecular signature. Human head and neck squamous cell carcinoma (HNSCC) cell lines, a mouse model with human HNSCC, and tissue from HNSCC patients previously treated with DDP monotherapy were used in the study. In order to demonstrate the role of MRN on DDP resistance, two cell lines with significantly different sensitivity to DDP were chosen. In vitro and in vivo studies were performed to evaluate whether the chemoresistant cell line experienced increased CSC levels after DDP treatment, and whether enhanced MRN complex mediated DNA repair could explain this differential response. In addition, we assessed whether disrupting the MRN complex could lead to downregulation of these disparate effects on MRN and DNA repair, in both the CSCs and the rest of the tumor cells, conferring increased sensitivity to DDP. We evaluated both MRN expression and CSC levels, and how they correlated with apoptosis levels in patient tissue resected three days after a three day course of induction DDP monotherapy. Our study demonstrates that CSC levels and MRN expression strongly correlate with chemoresistance in vitro, in vivo, and in human. Importantly, disruption of MRN leads to increased sensitivity of HNSCC cells to DDP treatment. In conclusion, we propose to elucidate a novel mechanism responsible for CSC mediated chemoresistance, which relies on enhanced DNA DSB repair via upregulation of the MRN complex. Our findings emphasize that disrupting this complex leads to increased sensitivity of HNSCC cells to DDP, potentially reducing the need for high, toxic doses of DDP used clinically and improving treatment outcomes. Citation Format: Danish Nagda, Shayanne A. Lajud, Taku Yamashita, Sanjeev Kumar, Jun Zheng, Peter Qiao, Orysia Bezpalko, Bert W. O'Malley, Daqing Li. The Mre11/Rad50/Nbs1 (MRN) complex: A critical mediator of chemoresistance and cancer stem cell progression in head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3748. doi:10.1158/1538-7445.AM2013-3748