High-grade serous ovarian carcinoma (HGSOC) often responds initially to poly (ADP-ribose) polymerase inhibitors (PARPi) such as olaparib, particularly in tumors with defects in homologous recombination (HR) DNA repair, but resistance to these drugs remains a major clinical challenge. A research team now reports a potential way around that problem, identified through an unusually broad search of already-approved medicines.
Writing in Experimental Hematology & Oncology, M. Chiappa, G. Damia and colleagues describe screening more than 1400 FDA-approved compounds to find agents capable of restoring olaparib sensitivity in resistant ovarian cancer cells. DNA topoisomerase I inhibitors (TOP1i) emerged as the most effective partner drugs in the screen.
The combination of TOP1 inhibitors with PARP inhibitors showed strong synergistic anticancer effects across multiple murine and human HGSOC models, the authors report. Notably, the synergy was observed regardless of the tumors’ HR status, meaning the strategy did not depend on the homologous recombination defects that typically predict response to PARP inhibitors alone.
According to the study, the combination was well tolerated in these models, an important consideration for any regimen intended to build on existing PARP inhibitor treatment.
Mechanistically, the paired drugs appeared to work primarily by inducing apoptosis and increasing DNA damage in the cancer cells, consistent with the idea that topoisomerase I inhibition and PARP blockade converge on lethal lesions in the genome.
Subject of Research: Combining PARP inhibitors with topoisomerase I inhibitors to overcome olaparib resistance in high-grade serous ovarian cancer
Article Title: Combination of PARPi and topoisomerase I inhibitors is highly effective in olaparib-resistant ovarian cancer
Article References: Chiappa, M., Villa, V., Sias, F., Grasselli, C., Sala, L., Canesi, S., Marabese, M., Mason, S., Dibitetto, D., Fruscio, R., & Damia, G. (2026). Combination of PARPi and topoisomerase I inhibitors is highly effective in olaparib-resistant ovarian cancer. Experimental Hematology & Oncology, 15(1), Article 94. https://doi.org/10.1186/s40164-026-00828-7
Image Credits: AI Generated
DOI: 10.1186/s40164-026-00828-7
Keywords: ovarian cancer, PARP inhibitors, olaparib resistance, topoisomerase I inhibitors, drug combination, high-grade serous ovarian carcinoma, homologous recombination, patient-derived xenografts, apoptosis, DNA damage, drug screening, preclinical models
News Source: Nathaniel Bowman. (October 29, 2026). Topoisomerase I Inhibitors Pair With PARP Drugs Against Resistant Ovarian Cancer. Scienmag.
