APOBEC3B enhances the efficacy of PARP inhibitors in elimination of ovarian cancer stem cell
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 synchronize efficiently with PARPi. In this study we knocked down of A3B in A2780 3D tumorsphere by lentiviral tranduction, followed by treated of DMSO control or Olaparib, and performed bulk RNA-sequencing to compare gene expression changes (n=3 for each condition). Overall design: RNA-sequecning of A2780 following lentiviral knockdown of A3B and the backbone control, followed by treatment of DMSO or Olaparib (n=3 for each conditon, total n=12).