Abstract 835: Epigenetic biomarkers of chemoresistance in colorectal cancer

Abstract

Abstract Resistance acquisition to chemotherapeutic agents is one of the main problems that come up during cancer treatment. The mechanisms of developing resistance are poorly understood, and the causes underlying the loss of sensitivity to common chemotherapy drugs are largely unknown. Promoter hypermethylation of DNA repair genes has been demonstrated to be an excellent biomarker of sensitivity to chemotherapy agents, being the epigenetic silencing of MGMT in gliomas the most remarkable example. In this study, we have focused our research on one of the most common cancer type, the colorectal cancer (CRC). Thus, we propose to assess how DNA methylation alterations can help to explain acquired resistance to oxaliplatin (OXA) in this type of tumours. To address this issue we used LoVo OXA sensitive and resistant cell lines (LoVoS_OXA vs. LoVoR_OXA). Using DNA genomic bisulfite sequencing we found that CpG islands located at some genes promoters (candidate genes) are unmethylated in LoVoS_OXA but hypermethylated in LoVoR_OXA, being these phenomena correlated with lower mRNA and protein expression in the resistant cell line. DNA promoter methylation of theses candidate genes was then checked by Methylation Specific PCR (MSP) in 25 human CRC tumour samples obtained from patients treated with FOLFOX (5-fluorouracil; leucovorin and oxaliplatin)(blind study). Remarkably, one candidate gene promoter hypermethylation was related with worse response to chemotherapy, poor overall survival and poor progression- free survival. In contrast, promoter hypermethylation of a second candidate gene was related with improved treatment response and survival rates. Being this an ongoing project, we are performing in vitro studies in order to check if changes in promoter hypermethylation can modulate cell sensitivity to OXA drug. The results obtained in this study can help to understand the biological processes leading to chemoresistance and also to the future management of cancer 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 835. doi:1538-7445.AM2012-835