Abstract
Late detection and tumor recurrence are major factors driving the lethality of high-grade serous ovarian carcinoma (HGSOC). PARP inhibitors (PARPi) have achieved significant clinical efficacy by selectively targeting DNA repair deficiencies in HGSOC patients with BRCA mutations and homologous recombination deficiency (HRD). However, a subset of patients ultimately develops resistance to PARPi, necessitating alternative effective treatment options. The mutational signatures of APOBEC3 family of DNA deaminases are widespread across a broad array of cancer types. Here, we report that cancer stem cell (CSC)-like tumorspheres exhibit reduced A3B expression compared to non-CSC adherent counterparts. Importantly, inhibition of A3B leads to PARPi resistance, elevated frequency of CSCs, and enhanced expression of stemness factors. In addition, we found that high A3B-expressing cells are under strong replication stress and thus synergize efficiently with PARPi. These studies reveal the important role A3B plays in regulating PARPi response.
Data availability
The RNA-sequencing dataset used in this study is available at GEO database (GEO309870).
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Acknowledgements
This work was supported by NIH/NCI 1R03CA270853, 1R01CA282792, and 1R03CA287274 (Q. Jiang); the JM Foundation (Q. Jiang); the Curebound Foundation (Q. Jiang); the Leukemia Research Foundation (Q. Jiang); the UCSD Senate Grants (2021 and 2022, Q. Jiang); the Sanford Stem Cell Institution (Q. Jiang); Pivot Pilot Grant (Q. Jiang), The Swedish Childhood Cancer Foundation (Barncancerfonden) TJ2014-0024 (F. Holm). L.A.C. is a Scholar of Blood Cancer United and is supported in part by NIH/NCI R37CA252040, NIH/NCI P30CA023100, and funding from the UC San Diego Sanford Stem Cell Institute. The authors wish to thank Jane Isquith for scientific discussion, the UCSD Institute for Genomic Medicine and the UCSD Center for Computational Biology & Bioinformatics (CTSA grant, UM1 TR005449) for Library Construction, Sequencing and Bioinformatics analyses. IGM Genomics Center, University of California, San Diego, La Jolla, CA, which is supported by NIH/NCI P30CA023100. This publication includes data generated at the IGM Genomics Center utilizing Illumina NovaSeq X Plus or 6000 instruments purchased with funding from a National Institutes of Health SIG grant (#S10 OD026929). Flow cytometry data were collected at the UCSD Moores Cancer Center flow cytometry facility, which obtained a BD FACSymphony S6 through support from the NIH (S10OD032316).
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Q.J., R.N.E., L.A.C., K.M.F., and F.H, designed the study and prepared the manuscript. C.L., M.R., L.L., H.Z., Q.J.Z, S.E., and Q.J. performed experiments and data analysis. K.M.F., R.S., S.E., and H.Z. performed the computational analysis.
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Rivera, M., Liu, L., Enlund, S. et al. APOBEC3B enhances the efficacy of PARP inhibitors in elimination of ovarian cancer stem cell. Sci Rep (2026). https://doi.org/10.1038/s41598-026-35939-y
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DOI: https://doi.org/10.1038/s41598-026-35939-y
