Abstract 4333: Metabolite profiling reveals druggable metabolic distinctions between basal-like and non-basal-like triple-negative breast cancers

Abstract

Abstract Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer that represents about 15-20% of all breast cancers. Because TNBC tumors do not express the estrogen or progesterone receptor and lack HER2 amplification, the disease is not responsive to current targeted therapies. The development of therapeutic approaches specific for TNBC is hindered by genetic heterogeneity, and significant efforts are being made to subtype the disease. To this end, we performed metabolite profiling (metabolomics) to characterize metabolic fingerprints within TNBC in order to define metabolic subtypes, and identify molecular drivers for the development of targeted therapies. We profiled twelve well-characterized TNBC-derived cell lines as well as a non-transformed, immortalized breast cell line and two primary human mammary epithelial cell lines. Those cancer cell lines recapitulate all 7 genetic subtypes of TNBC which were proposed recently based on mRNA gene expression profiles (1). Our approaches used and data generated have implications for drug target discovery. Hierarchical clustering based on high quality intracellular metabolites clearly and reproducibly segregated the TNBC cell lines from the non-transformed lines. Alterations in energy utilization, lipid metabolism, and other pathways of importance to highly proliferative cells differed significantly from the control cell line MCF-10A. In addition, TNBC cell lines segregated into two discrete groups, suggesting the existence of two major metabolic subtypes of TNBC, which correlated with basal-like vs. non-basal-like gene expression. Metabolites like glutamate and glutamine, serine, glycine, trans-4-hydroxyproline, 5-oxoproline, several complex lipids (phosphatidylcholines and sphingomyelins), myo-inositol, polyamines spermidine and putrescine represented metabolites differing significantly between TNBC metabolic subtypes. Ongoing studies are evaluating whether these differences represent dependencies with therapeutic relevance. Metabolite profiling was also used to identify potential metabolic liabilities generated by treatment with clinical kinase inhibitors. Response of the metabolome to treatment with rapamycin, sorafenib, imatinib, and lapatinib in four genetically diverse TNBC cell lines and MCF-10A control cell lines revealed specific drug-induced metabolic alterations. Co-targeting kinases and metabolic targets may offer an approach to synthetic lethality with a reduced likelihood for the development of drug resistance. (1) (Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 2011;121) Citation Format: Alexander Beatty, Lauren Fink, Ulrike Rennefahrt, Alexander Strigun, Erik Peter, Hajo Schiewe, Regina Reszka, Jeffrey R. Peterson. Metabolite profiling reveals druggable metabolic distinctions between basal-like and non-basal-like triple-negative breast cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4333. doi:10.1158/1538-7445.AM2014-4333