Abstract B055: Metabolic stratification of human breast tumors reveal subtypes of clinical and therapeutic relevance

Abstract

Abstract Metabolic heterogeneity in breast cancer has limited the deployment of metabolic therapies. To enable patient stratification, we studied global metabolic landscape of breast cancer (N>3000 combined) and identified three metabolic subtypes with increasing degrees of metabolic deregulation. M1 exhibited deregulated bile acid biosynthesis whereas M2 showed reliance on methionine pathway and M3 was found to be the most metabolically aggressive engaging fatty, nucleotide, and glucose metabolism. Extent of metabolic deregulation correlated strongly with tumor aggressiveness and patient outcome Moreover bile acid biosynthesis predicted less aggressive tumors with better prognosis while pyrimidine metabolism predicted the opposite trend. Notably this pattern was reproducible in independent datasets and in vivo tumor metabolite data. Genomic characterization of metabolic subtypes revealed TP53 mutation and MYC amplification as the strongest predictor of metabolic deregulation. Using machine learning, we identified robust and generalizable signatures that recaptured metabolic subtypes in tumors and cell lines. Surprisingly, the least deregulated M1 subtype was not found to be represented by any of the 50 cell line models analyzed. Experimental inhibition of metabolic pathways demonstrated subtype specific sensitivity and improved combinatorial efficacy of chemotherapeutic drugs. In addition, breast cancer cell lines representing metabolic subtypes revealed therapeutically relevant drugs. Taken together, this work presents metabolic stratification of breast cancer patients that may have implications in predicting patient outcome and designing precision therapies. Citation Format: Mohammad A Iqbal, Shumaila Siddiqui, Kirk Smith, Prithvi Singh, Bhupender Kumar, Salem Chouaib, Sriram Chandrasekaran. Metabolic stratification of human breast tumors reveal subtypes of clinical and therapeutic relevance [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B055.