25 Proffered Paper: Involvement of Epigenetics in the Early Stages of NSCLC Development

diversity of human cancers and for which detailed genetic and pharmacological annotation is available. Here we describe the Cancer Cell Line Encyclopedia (CCLE), a comprehensive resource of human cancer models for basic and translational research that encompasses gene expression, chromosomal copy number and massively parallel sequencing data from 947 human cancer cell lines spanning many tumor types. When coupled with pharmacological profiles for 24 anticancer drugs across 479 of the cell lines, this collection allowed identification of genetic, lineage, and gene-expression-based predictors of drug sensitivity through systematic integration of the genomic and pharmacologic datasets. In addition to rediscovering molecular features known to predict response to several drugs, we uncovered novel potential biomarkers of sensitivity and resistance to both targeted agents and chemotherapy drugs. For instance, our analysis revealed new in vitro markers associated with sensitivity to MEK inhibitors in NRAS-mutant cell lines. Also, we found that response to topoisomerase 1 inhibitors seems to be predicted largely by expression of a single gene. Finally, we observed that tissue lineage is a key predictor for sensitivity to certain compounds, providing rationale for clinical trials of these drugs in particular cancer types. Together, our results indicate that large, annotated cell-line collections may help to identify biomarkers that allow the stratification of patients for appropriate drug treatment at the preclinical stage. The generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of ‘personalized’ therapeutic regimens.