Abstract P5-10-01: A systems approach to combine genomics and emerging therapeutics to discover new treatments for TNBC

Genomic analyses of patient tumors have unearthed an overwhelming number of recurrent somatic alterations in genes that undoubtedly have dramatic effects on breast tumor biology, clinical outcomes and responses to therapeutics. In triple negative breast cancer (TNBC), there is an urgent need to translate this emerging patient genomic data into new therapeutic paradigms. To develop genotype-specific therapies, we have established an isogenic cell-line drug screen that measures the impact of gene activation on a panel of emerging, clinically relevant compounds targeting a variety of cancer pathways. We seek to uncover genotype-dependent sensitivity to drugs, synthetic lethal relationships, and validate in breast cancer cells and in vivo mouse models. We focused on emerging compounds that are already approved or in testing for human use and we expect that this work will serve as a prelude to one or more clinical trials in TNBC. RESULTS: We have developed a synthetic-lethal interaction mapping strategy to uncover the impact of gene activation on responses to a panel of emerging therapeutics. We believe that this approach can identify core synthetic lethal interactions which underlie drug sensitivity and can be used as a foundation to identify patient populations that will selectively respond to drug treatments. We have developed a high-throughput screening platform that can rapidly and accurately assess the proliferative capacity of cell lines in response to a panel of inhibitors. We have generated a panel of isogenic cell lines which closely mimic the impact of recurrent gene mutations and overexpression common in breast cancer. We have currently generated 23 cell lines expressing wild-type and/or mutant forms of these genes. To date we have screened 12 known oncogenes against our panel of 94 emerging therapeutic compounds. Using this systems approach, the resulting interaction map highlights both known and novel connections between oncogene activation and drug responses and provides a modular roadmap for the exploration of synthetic lethal relationships. Based on the coordinate activity of multiple drugs targeting the same pathway, we identified oncogenes that can drive resistance to EGFR inhibitors and PI3K/AKT inhibitors. We also recapitulated a known synthetic lethal relationship between MYC and CDK inhibition which we have previously described and we are now evaluating in a clinical trial. Therefore, our approach identified both resistance and synthetic lethal relationships that have been independently described, indicating that this platform is a good model for predicting synthetic lethality in vivo. Several novel and previously uncharacterized connections were also uncovered, including novel connections between MYC activity and several promising drugs in clinical development. Synthetic-lethal interactions discovered using this chemical-genetic systems approach and their mechanistic validation will be described in the presentation. Furthermore, the important role of patient advocacy in developing this project will be described. CONCLUSION: A novel systems biology approach that uses chemical-genetic maps of oncogenes and emerging therapeutics can define synthetic-lethal interactions and actionable therapeutics for breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-10-01.