Abstract
Several poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors are now in clinical use for tumours with defects in BReast CAncer genes BRCA1 or BRCA2 that result in deficient homologous recombination repair (HRR). Use of olaparib, niraparib or rucaparib for the treatment of high-grade serous ovarian cancer, including in the maintenance setting, has extended both progression free and overall survival for women with this malignancy. While different PARP inhibitors (PARPis) are mechanistically similar, differences are apparent in their chemical structures, toxicity profiles, PARP trapping abilities and polypharmacological landscapes. We have treated ovarian cancer cell line models of known BRCA status, including the paired cell lines PEO1 and PEO4, and UWB1.289 and UWB1.289+BRCA1, with five PARPis (olaparib, niraparib, rucaparib, talazoparib and veliparib) and observed differences between PARPis in both cell viability and cell survival. A cell line model of acquired resistance to veliparib showed increased resistance to the other four PARPis tested, suggesting that acquired resistance to one PARPi may not be able to be rescued by another. Lastly, as a proof of principle, HRR proficient ovarian cancer cells were sensitised to PARPis by depletion of BRCA1. In the future, guidelines will need to emerge to assist clinicians in matching specific PARPis to specific patients and tumours.
Highlights
The advent of pharmacological inhibitors of the DNA repair enzyme poly polymerase (PARP) has heralded major therapeutic advances for malignancies that have defects in components of homologous recombination repair (HRR) pathways [1,2,3]
Specific improvements have been seen in both progression free and overall survival for women with high-grade serous ovarian cancer (HGSOC) treated with a PARP inhibitors (PARPis) [37,38,39,40,41]
Currently there is no clear rationale regarding which PARPi to use, for which ovarian cancer patients beyond Food and Drug Administration (FDA) endorsement of olaparib, rucaparib or niraparib when a mutation is present in BRCA1 or BRCA2 after first-line platinum-based chemotherapy or as maintenance therapy [30,42]
Summary
The advent of pharmacological inhibitors of the DNA repair enzyme poly (adenosine diphosphate-ribose) polymerase (PARP) has heralded major therapeutic advances for malignancies that have defects in components of homologous recombination repair (HRR) pathways [1,2,3]. BRCA1 methylated tumours are sensitive to PARP inhibition [8], as are tumours with mutations in other genes that function in repair of double strand breaks (DSBs), including RAD51C, RAD51D, ATM and PALB2, where tumours are described as having a “BRCAness” phenotype [8,9,10]. With this broadening concept of BRCAness, other malignancies are being investigated to assess sensitivity to PARP inhibitors, including colorectal, upper gastrointestinal and acute myeloid leukemia [1,11,12,13]. We manipulated HRR by down-regulating BRCA1 in BRCA1 wild-type cells, including in OVCAR-3 cells known to harbor a CCNE1 amplification and be HRR proficient, to determine whether we could sensitise cells to PARP inhibitors
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