High-grade serous ovarian cancer (HGSOC) is the most common form of ovarian cancer diagnosed in patients worldwide. Patients with BRCA1/2-mutated HGSOC have benefited from targeted treatments such as poly(ADP-ribose) polymerase inhibitors (PARPi). Despite the initial success of PARPi-based ovarian cancer treatment regimens, approximately 70% of patients with ovarian cancer relapse and the 5-year survival rate remains at 30%. PARPi exhibit variable treatment efficacy and toxicity profiles. Furthermore, the off-target effects of PARP inhibition have not yet been fully elucidated, warranting further study of these classes of molecules in the context of HGSOC treatment. Highly reproducible quantitative mass spectrometry-based proteomic workflows have been developed for the analysis of tumor tissues and cell lines. To detect the off-target effects of PARP inhibition, we conducted a quantitative mass spectrometry-based proteomic analysis of a BRCA1-mutated HGSOC cell line treated with low doses of two PARPi, niraparib and rucaparib. Our goal was to identify PARPi-induced protein signaling pathway alterations toward a more comprehensive elucidation of the mechanism of action of PARPi beyond the DNA damage response pathway. A significant enrichment of nuclear and nucleoplasm proteins that are involved in protein binding was observed in the rucaparib-treated cells. Shared upregulated proteins between niraparib and rucaparib treatment demonstrated RNA II pol promoter-associated pathway enrichment in transcription regulation. Pathway enrichment analyses also revealed off-target effects in the Golgi apparatus and the ER. The results from our mass spectrometry-based proteomic analysis highlights notable off-target effects produced by low-dose treatment of BRCA1-mutated HGSOC cells treated with rucaparib or niraparib.
|Original language||English (US)|
|Number of pages||9|
|Journal||Journal of the American Society for Mass Spectrometry|
|State||Published - Feb 2 2022|
Bibliographical notePublisher Copyright:
© 2022 American Chemical Society.
- PARP inhibitor (PARPi)
- mass spectrometry
- ovarian cancer
- tandem mass tags (TMT)