Abstract 2573: Molecular mechanism of cisplatin-based chemoresistance with human head and neck cancer: A translational clinical study

Abstract

Abstract (Background) Cisplatin is a commonly used chemotherapy agent for many kinds of cancers including head and neck cancer. Chemoresistance to cisplatin significantly contributes to treatment failure in clinical practice. The MRE11/RAD50/NBS1 (MRN) complex is well known a major DNA repair system. Our previous in vitro study shows that enhanced DNA repairing by MRN is a critical molecular mechanism for cisplatin-based chemoresistance. The present study further investigates if the finding of enhanced DNA repairing is responsible for cisplatin-based chemoresistance with human head and neck squamous cell carcinoma (HNSCC) in an animal model and, more important, if this finding correlates to the clinical study with patients who suffer from HNSCC. (Methods) An animal model with human HNSCC was used for this study. Tumor volume changes were measured before and after cisplatin treatment. Immunohistochemistry studies were carried out for detecting the expression levels of MRN and apoptosis. The chemoresistant profile of the tumor model was established depending on these studies. The patients with HNSCC who initially received cisplatin monotherapy along with the patients without having cisplatin treatment were investigated. Immunohistochemistry studies were carried out for detecting the expression levels of MRN and apoptosis. These results were carefully analyzed by using a linear regression model with random effects to compare with established animal tumor model and in vitro findings. (Results) Our animal model with human HNSCC demonstrated that chemoresistance to cisplatin is associated with increased expression levels of MRN after cisplatin treatment (p<0.0001(MRE11), p<0.0001(RAD50), p<0.0001(NBS1)). In addition, the resistant tumors showed decreased levels of apoptosis after cisplatin treatment (p<0.0001). Our clinical study confirms these findings as shown that patients with HNSCC had increased expression of MRN when developing cisplatin chemoresistnace. (Conclusion) It is strongly suggested that increased expression levels of MRN proteins after cisplatin treatment are associated with a resistant phenotype in the human HNSCC. Our study presents important findings that will facilitate a better understanding of the molecular mechanisms underlying tumor cell resistance to chemotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2573.