Abstract 1366: Discovery of biomarkers for antitumor drug resistance using 450K methylation data of NCI60

Abstract

The National Cancer Institute Antitumor Cell line panel NCI60 is a very frequently used collection of cancer cell lines that has been largely characterized in different biological aspects. Data from proteomic and RNA expression analyses of this panel is already available to the scientific community. Also, the IC50 data for more than 100,000 different compound treatments is accessible in the developmental therapeutic program of NCI (dtp). However, very little has been explored about the epigenetic component of this panel. We have performed a thorough correlational study combining the available molecular information of NCI60, the data of our 450K NCI60 dataset and the IC50 data from the dtp to discover candidate genes for new biomarkers of resistance to antitumor agents. Finding new biomarkers to determine the most probable response to the therapy seems to be a key stage in the development of personalized medicine. Due to its stability and how easy it is to detect its level of methylation, DNA methylation changes appear to be a perfect candidate mark for the construction of this new generation of biomarkers. In this study we obtained multiples candidate genes whose methylation correlated to resistance to different drugs. In order to perform validation analyses we chose a gene that showed a strong positive correlation with the resistance to several DNA damage agents (DDA).Using overexpression and silencing assays we were able to demonstrate that the expression of this gene has a profound influence on the cell sensitivity to the DDA. Furthermore, through gene expression validation assays, such as 5-azacytidine treatments, we demonstrated that the promotor methylation of this gene is associated to its non-expression. In addition, we observed that this gene methylation correlates with a lower overall survival in an ovarian cancer cohort treated with platinum agents. Little is known about our candidate gene but it seems to be related to the DNA repair machine and also to have a function in the cell cycle control. These features could give an explanation to the importance of its presence in the response to DDA treatment. Our studies show that the analysis of DNA methylation changes in cancer cells in combination with other molecular alterations can be used in correlational studies to find trustworthy biomarkers for antitumor drug resistance. Citation Format: Vanesa Nogales, Catia Moutinho, Anna Martinez-Cardús, Sudhir Varma, J. Keith Killian, William C. Reinhold, Paul S. Meltzer, Yves Pommier, Manel Esteller. Discovery of biomarkers for antitumor drug resistance using 450K methylation data of NCI60. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1366. doi:10.1158/1538-7445.AM2014-1366