Abstract 4370: Protein kinase inhibitor screening uncovers differential kinase dependencies in triple negative breast cancer (TNBC).

Abstract

Abstract Triple-negative breast cancer (TNBC) constitutes approximately 20% of all breast cancer and disproportionately affects younger women and African-American women. These tumors, negative for estrogen receptor, progesterone receptor, and Her2 amplification, are resistant to standard targeted treatments, and the need for new therapeutic targets for this tumor type is urgent. Within the TNBC patient population, there is variability in response to treatment, and it is unclear what molecular features of the disease lead to this heterogeneity. Protein kinases are often amplified and/or mutated in human cancers, and they are attractive therapeutic targets due to their enzymatic activity and widespread expression. We have screened a library of small-molecule kinase inhibitors against a panel of 12 TNBC cell lines and 3 control cell lines in duplicate in cell viability assays. We generated dose-response curves and half maximal inhibitory concentration (IC50) values for each compound-cell line pair. The results support a heterogeneous dependence of different TNBC cell lines on specific kinases. Statistical analysis identifies significantly over-represented kinase targets and pathways in subsets of TNBC cell lines following inhibitor treatment. A number of compounds show selective toxicity for TNBC cell lines and suggest targetable kinase dependencies. Kinase inhibitor sensitivity in TNBC does not appear to correlate with gene expression patterns, suggesting alternative mechanisms for TNBC heterogeneity. Sequencing data and other biomarkers databases will be mined for correlations with sensitivity to kinase inhibition in TNBC. Thus this study will identify new potential therapeutic targets and biomarkers for TNBC. Citation Format: Lauren S. Fink, Alexander Beatty, Karthik Devarajan, Suraj Peri, Jeffrey R. Peterson. Protein kinase inhibitor screening uncovers differential kinase dependencies in triple negative breast cancer (TNBC). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4370. doi:10.1158/1538-7445.AM2013-4370