PARP Inhibitors Display Differential Efficacy in Models of BRCA Mutant High-Grade Serous Ovarian Cancer
| Autor: | Tao Xie, Kristie-Ann Dickson, Deborah J. Marsh, Yue Ma, Christian R. Evenhuis |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Veliparib
endocrine system diseases QH301-705.5 Poly(ADP-ribose) Polymerase Inhibitors talazoparib olaparib Models Biological Catalysis Article Olaparib homologous recombination repair Inorganic Chemistry chemistry.chemical_compound 0399 Other Chemical Sciences 0604 Genetics 0699 Other Biological Sciences Breast cancer Cell Line Tumor medicine Talazoparib Humans Viability assay Biology (General) Physical and Theoretical Chemistry Rucaparib QD1-999 Molecular Biology Spectroscopy veliparib BRCA2 Protein Ovarian Neoplasms Chemical Physics business.industry BRCA1 Protein Organic Chemistry General Medicine medicine.disease BRCA1 BRCA2 rucaparib Computer Science Applications Chemistry PARP inhibitor chemistry Mutation Cancer research Female business Homologous recombination niraparib |
| Zdroj: | International Journal of Molecular Sciences Volume 22 Issue 16 International Journal of Molecular Sciences, Vol 22, Iss 8506, p 8506 (2021) |
| ISSN: | 1422-0067 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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