The Differential Metabolic Signature of Breast Cancer Cellular Response to Olaparib Treatment

SIMPLE SUMMARY: Breast cancer remains a leading cause of female cancer related mortality worldwide. Loss of genomic stability and dysregulation of cellular metabolism are well-recognized features of breast cancer, presenting an opportunity to study the drivers of breast cancer progression and resistance to chemotherapy. The overarching goal of this work is to perform combined analysis of DNA damage repair and cellular metabolism in response to olaparib treatment in a panel of breast cancer cell lines. By applying a combined untargeted metabolomics and molecular biology approach, our findings show dysregulation of amino acid metabolism and metabolic reprogramming from glycolysis to amino acid utilization to be a common feature in all breast cancer cell lines examined, some of which are consistent with findings from the analysis of clinical breast cancer tumours. Functional assessment of genetic alterations offers the scope to design new prognostic tools and inform the design of new chemotherapies or drug combinations. ABSTRACT: Metabolic reprogramming and genomic instability are key hallmarks of cancer, the combined analysis of which has gained recent popularity. Given the emerging evidence indicating the role of oncometabolites in DNA damage repair and its routine use in breast cancer treatment, it is timely to fingerprint the impact of olaparib treatment in cellular metabolism. Here, we report the biomolecular response of breast cancer cell lines with DNA damage repair defects to olaparib exposure. Following evaluation of olaparib sensitivity in breast cancer cell lines, we immunoprobed DNA double strand break foci and evaluated changes in cellular metabolism at various olaparib treatment doses using untargeted mass spectrometry-based metabolomics analysis. Following identification of altered features, we performed pathway enrichment analysis to measure key metabolic changes occurring in response to olaparib treatment. We show a cell-line-dependent response to olaparib exposure, and an increased susceptibility to DNA damage foci accumulation in triple-negative breast cancer cell lines. Metabolic changes in response to olaparib treatment were cell-line and dose-dependent, where we predominantly observed metabolic reprogramming of glutamine-derived amino acids and lipids metabolism. Our work demonstrates the effectiveness of combining molecular biology and metabolomics studies for the comprehensive characterisation of cell lines with different genetic profiles. Follow-on studies are needed to map the baseline metabolism of breast cancer cells and their unique response to drug treatment. Fused with genomic and transcriptomics data, such readout can be used to identify key oncometabolites and inform the rationale for the design of novel drugs or chemotherapy combinations.