Proteomic Analysis Reveals Low-Dose PARP Inhibitor-Induced Differential Protein Expression in BRCA1-Mutated High-Grade Serous Ovarian Cancer Cells

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.