Abstract 5724: Dual inhibition of PARP and STAT3 as a novel therapeutic approach for triple-negative breast cancer cells

Triple-negative breast cancer (TNBC) is a highly aggressive and metastatic subtype of breast cancer with limited therapeutic options, contributing significantly to patient mortality. This highlights an urgent need for novel treatment strategies. Olaparib, an FDA-approved poly ADP-ribose polymerase (PARP) inhibitor, is effective in human epidermal growth factor receptor (HER2) negative breast cancer, especially in BRCA-mutated subtypes. However, BRCA-mutant TNBC could eventually develop resistance to PARP inhibitors. We recently found that Olaparib treatment induces elevated IL-6 levels in TNBC cells, which may generate resistance to PARP inhibitors and reduce their effectiveness. Furthermore, knockdown of STAT3, a main downstream effector of IL-6 signaling, enhanced TNBC sensitivity to Olaparib. This study explored the combination of Olaparib and a novel orally bioavailable small-molecule STAT3 inhibitor, LLL12B, in human and murine TNBC cell lines. Both Olaparib and LLL12B independently reduced cell viability, migration, and invasion, but their combination demonstrated significantly greater efficacy than either treatment alone. These results support that dual inhibition of PARP and STAT3 is a novel targeted therapeutic strategy for TNBC. Citation Format: Changyou Shi, Li Pan, Satomi Amano, Jiayuh Lin. Dual inhibition of PARP and STAT3 as a novel therapeutic approach for triple-negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5724.