APOBEC3B Enhances PARP Inhibitor Response by Suppressing Ovarian Cancer Stem Cells

Poly(ADP-ribose) polymerase inhibitors (PARPi) provide substantial benefit to high-grade serous ovarian cancer (HGSOC) patients with BRCA mutations or homologous recombination deficiency (HRD), yet resistance remains a major clinical challenge. Cancer stem cells (CSCs) are thought to drive recurrence and therapeutic failure, highlighting the need to define molecular determinants governing CSC biology and PARPi response. APOBEC3 (A3) cytidine deaminases, particularly A3B, represent key enzymatic mutators in cancer and are highly expressed in HGSOC. However, their roles in CSCs and therapeutic sensitivity remain poorly understood. Using previously published scRNA-seq datasets from six HGSOC patients, including one BRCA2-mutant case, we found that A3B is the predominantly expressed A3 family member, followed by A3C and A3A. In patient-derived xenografts (PDXs) and cell lines, CSC-enriched tumorspheres consistently exhibited reduced A3B levels relative to adherent non-CSC cells, whereas other A3s showed no CSC-specific changes. This pattern mirrors observations in myeloproliferative neoplasms, where stem cell populations display reduced A3 mutational burden relative to bulk tumor cells. Functionally, A3B knockdown increased tumorsphere formation and SOX2 expression, indicating that low A3B supports a self-renewing CSC state. Notably, among three HGSOC PDX models, only OV033 readily formed tumorspheres and exhibited the highest A3B expression, suggesting that BRCA status, HRD, and other genomic features may influence both tumorsphere capacity and A3B levels. We further demonstrate that A3B loss promotes olaparib tolerance by reducing A3B-induced replication stress in S/G2 cell line tumorspheres. Because PARPi induces ssDNA accumulation and replication stalling, A3B-high cells may experience increased DNA damage under PARPi, contributing to heightened sensitivity. This aligns with clinical data linking A3B overexpression to improved platinum responses. Together, these findings support A3B expression and activity as potential biomarkers for predicting PARPi response in HGSOC. In conclusion, our findings position A3B as a critical molecular switch linking CSC biology to PARPi response, revealing an immediately actionable biomarker and therapeutic vulnerability in HGSOC. Citation Format: Maria Rivera, Lucy Liu, Chae-Eun Lim, Sabina Enlund, Haoran Zhang, Kaifu Yang, Roman Sasik, Kathleen Fisch, Frida Holm, Leslie A. Crews, Qingfei Jiang. APOBEC3B enhances PARP inhibitor response by suppressing ovarian cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1752.