Carly A. I. Twigg

Global Proteomic Determination of the Poly-Pharmacological Effects of PARP Inhibitors Following Treatment of High-Grade Serous Ovarian Cancer Cells

High-grade serous ovarian cancer (HGSOC) is the most commonly diagnosed ovarian cancer subtype. Approximately half of all patients diagnosed with HGSOC are deficient in homologous recombination (HR), harbor BRCA1/2 mutations, and are treated with poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis). FDA-approved PARPis Olaparib, Niraparib, and Rucaparib all contribute to adverse effects in patients due to their poly-pharmacological properties. This feature necessitates investigation of global protein responses to PARPi treatment beyond DNA repair in the context of BRCA mutational status and HR deficiency. We sought to determine the landscape of differential PARPi-induced proteomes in HGSOC cells exhibiting different BRCA1/2 mutational statuses. Here, we applied immunofluorescence microscopy to detect γH2AX, Rad51, and geminin foci as markers of DNA damage and repair upon treatment of HGSOC cells with IC50 doses of PARPis. Global proteome perturbations upon PARPi treatment were measured using quantitative mass spectrometry-based proteomics. The proteomic data highlighted cell line effects, masking high-dose PARPi treatment response. Interrogation of PARPi response within biological pathways identified through gene set enrichment analysis (GSEA) revealed significant changes to proteins involved in Epithelial–Mesenchymal Transition (EMT), E2F targets, and cholesterol homeostasis. Our study establishes proteomic evidence supporting the poly-pharmacological characteristics of Niraparib, Olaparib, and Rucaparib in HGSOC cells.