The Poly (ADP-Ribose) Polymerase inhibitor Veliparib and Radiation Cause Significant Cell Line Dependent Metabolic Changes in Breast Cancer Cells

Breast tumors are characterized into different subtypes based on their surface marker expression, which affects their prognosis and treatment. For example, triple negative breast cancer cells (ER-/PR-/Her2-) show reduced susceptibility towards radiotherapy and chemotherapeutic agents. Poly (ADP-ribose) polymerase (PARP) inhibitors have shown promising results in clinical trials, both as single agents and in combination with other chemotherapeutics, in several subtypes of breast cancer patients. PARP1 is involved in DNA repair, apoptosis, and transcriptional regulation and an understanding of the effects of PARP inhibitors, specifically on metabolism, is currently lacking. Here, we have used NMR-based metabolomics to probe the cell line-specific effects of PARP inhibitor and radiation on metabolism in three distinct breast cancer cell lines. Our data reveal several cell line independent metabolic changes upon PARP inhibition, including an increase in taurine. Pathway enrichment and topology analysis identified that nitrogen metabolism, glycine, serine and threonine metabolism, aminoacyl-tRNA biosynthesis and taurine and hypotaurine metabolism were enriched after PARP inhibition in the three breast cancer cell lines. We observed that the majority of metabolic changes due to radiation as well as PARP inhibition were cell line dependent, highlighting the need to understand how these treatments affect cancer cell response via changes in metabolism. Finally, we observed that both PARP inhibition and radiation induced a similar metabolic response in the HCC1937 (BRCA mutant cell line), but not in MCF-7 and MDAMB231 cells, suggesting that radiation and PARP inhibition share similar interactions with metabolic pathways in BRCA mutant cells. Our study emphasizes the importance of differences in metabolic responses to cancer treatments in different subtypes of cancers.