Abstract 2620: The Cancer Cell Line Encyclopedia project: From integrative cancer genomics to personalized cancer therapy

Abstract Cancer genome characterization efforts such as The Cancer Genome Atlas project are rapidly improving our knowledge of tumor genetic alterations. With the expanded use of massively parallel sequencing, the catalogue of known genetic alterations in cancer is expected to expand at an accelerating rate. In this context, the emphasis is shifting towards systematic identification of the genes and pathways targeted by recurrent genetic alterations, their functional impact in tumor biology, and the resulting cellular dependencies that might be exploited therapeutically. Anticipating the need for a companion resource to systematically probe tumor biology armed with cancer genomics knowledge, we have assembled a compendium of experimentally tractable cancer model systems consisting of ∼1000 human cancer cell lines and performed extensive genomic analysis (at the level of gene expression, DNA copy number and mutations) coupled with pharmacological profiling. This resource, which we call the Cancer Cell Line Encyclopedia (CCLE), is being used not only to identify the putative targets of prevalent genetic alterations, but also to systematically link the presence or absence of certain genetic alterations to drug sensitivity or resistance. To date, we have identified several previously unappreciated genomic predictors of response or intrinsic resistance to targeted anticancer agents. For instance, through integrative analysis, we have discovered additional mechanisms that may underlie sensitivity to MET inhibitors, beyond amplification of the MET receptor, highlighting the fact that response prediction in the clinic may require assessment of multiple variables. We have also broadened the potential relevance of known predictive biomarkers that might provide a rationale for future genotype-driven clinical trials. As an example, we have expanded on existing knowledge of resistance to receptor tyrosine kinase (RTK) inhibitors, showing that the presence of RAS mutations may predict lack of response to a broad spectrum of RTK inhibitors in addition to EGFR inhibitors. This work demonstrates that pharmacological profiling of large, genomically-annotated cancer model systems may uncover new tumor dependencies as well as positive and negative predictors of drug response. The results of this study are being made publicly available at a CCLE online portal, with the hope they will become a valuable resource for the cancer community to propel translation of the knowledge generated through in vitro integrative genomics into personalized cancer medicine. 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 2620.