Abstract 1116: Oncogene signatures identify novel therapeutic targets and combinatorial strategies in breast cancer

Abstract

Abstract During the course of tumorigenesis, cancer cells acquire a large number of genetic and epigenetic alterations. A subset of these alterations results in the generation of driver oncogenes that play critical roles in initiating and maintaining the transformed phenotype. We hypothesize that most solid tumors are simultaneously driven by multiple driver oncogenes that together form an oncogene network and that durable therapies for solid tumors will need to target multiple oncogenes. Identifying multiple driver oncogenes from among the large number of mutated/amplified genes present in most solid tumors is a nontrivial task that will require novel approaches. In this work, we have combined genome-wide, RNAi-based dropout screens with copy number, expression and exome sequencing analysis to identify the full complement of driver oncogenes that function in a panel of breast cancer cell lines. The panel of cell lines used for this study is the SUM panel of breast cancer cells which contains 10 cell lines and includes representatives of HER2 positive, ER positive, and triple negative breast cancer subtypes. For each line we have identified multiple activated driver oncogenes that when combined define a complete oncogene signature for the cell line. All of the oncogene signatures contain both well-characterized oncogenes that are known to play a role in breast cancer as well as novel driver genes that do not have a well-characterized role in breast cancer. Subsequent work has confirmed the role of several of the novel driver oncogenes including the epigenetic modifier KAT6A and the apoptotic regulator BCL2L1. Additionally, we show that the cell line oncogene signatures can be used to successfully predict sensitivity of individual cell lines to small molecule inhibitors. Predictions of sensitivity to inhibitors were confirmed through the integration of oncogene signatures with published data from large-scale drug screens across numerous cancer cell lines. Finally, we demonstrate the utility of oncogene signatures through their use in the design of novel therapeutic strategies that effectively reduce cancer cell viability. Citation Format: Stephen Guest, Zachary Kratche, Jonathan Irish, Aliccia Bollig-Fischer, Elizabeth Garrett-Mayer, Stephen Ethier. Oncogene signatures identify novel therapeutic targets and combinatorial strategies in breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1116. doi:10.1158/1538-7445.AM2015-1116