ArticleCell death & disease2024
Onvansertib treatment overcomes olaparib resistance in high-grade ovarian carcinomas.
Article in Cell death & disease, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- Review
- Combination of PARPi and topoisomerase I inhibitors is highly effective in olaparib-resistant ovarian cancer.Experimental hematology & oncology · 2026Article
- Interplay Between Poly(ADP-ribosyl)ation and Specific Inner Cellular Events That Suggest Combination Strategies for Overcoming PARP Inhibitor Resistance.Pharmaceutics · 2026Review
- Clinical application of PARP inhibitors and emerging strategies to overcome resistance: a pan-cancer perspective.Biomarker research · 2026Review
- Targeting PLK1 Reduces MMP10 to Enhance Radiosensitivity in HPV- Head and Neck Cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Article
- PLK1 or WEE1 inhibition targets homologous recombination repair proficiency in BRCA1/2 wild-type high-grade serous ovarian cancer.Cell death & disease · 2025Article
- Proteins involved in cell division have broad developmental functions.Developmental biology · 2025Article
- PLK1 inhibition enhances gemcitabine-induced apoptosis through PLK1-dependent ERK1/2-Bim and AKT1/Noxa signals in pancreatic cancer cells.Medical oncology (Northwood, London, England) · 2025Article
- Onvansertib-Based Second-Line Therapies in Combination with Gemcitabine and Carboplatin in Patient-Derived Platinum-Resistant Ovarian Carcinomas.International journal of molecular sciences · 2025Article
- Onvansertib and Navitoclax Combination as a New Therapeutic Option for Mucinous Ovarian Carcinoma.International journal of molecular sciences · 2025Article
- Clinical relevance of PLK1 in epithelial ovarian cancer.Frontiers in pharmacology · 2025Review
- Editorial: Innovative drug combinations for enhanced solid tumor treatment efficacy.Frontiers in oncology · 2025Article
- Article
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22 authors.
Funding
Abstract
Occurrence of resistance to olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor (PARPi) approved in ovarian carcinoma, has already been shown in clinical settings. Identifying combination treatments to sensitize tumor cells and/or overcome resistance to olaparib is critical. Polo-like kinase 1 (PLK1), a master regulator of mitosis, is also involved in the DNA damage response promoting homologous recombination (HR)-mediated DNA repair and in the recovery from the G2/M checkpoint. We hypothesized that PLK1 inhibition could sensitize tumor cells to PARP inhibition. Onvansertib, a highly selective PLK1 inhibitor, and olaparib were tested in vitro and in vivo in BRCA1 mutated and wild-type (wt) ovarian cancer models, including patient-derived xenografts (PDXs) resistant to olaparib. The combination of onvansertib and olaparib was additive or synergic in different ovarian cancer cell lines, causing a G2/M block of the cell cycle, DNA damage, and apoptosis, much more pronounced in cells treated with the two drugs as compared to controls and single agents treated cells. The combined treatment was well tolerated in vivo and resulted in tumor growth inhibition and a statistically increased survival in olaparib-resistant-BRCA1 mutated models. The combination was also active, although to a lesser extent, in BRCA1 wt PDXs. Pharmacodynamic analyses showed an increase in mitotic, apoptotic, and DNA damage markers in tumor samples derived from mice treated with the combination versus vehicle. We could demonstrate that in vitro onvansertib inhibited both HR and non-homologous end-joining repair pathways and in vivo induced a decrease in the number of RAD51 foci-positive tumor cells, supporting its ability to induce HR deficiency and favoring the activity of olaparib. Considering that the combination was well tolerated, these data support and foster the clinical evaluation of onvansertib with PARPis in ovarian cancer, particularly in the PARPis-resistant setting.
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