Napabucasin targets resistant triple negative breast cancer through suppressing STAT3 and mitochondrial function.

Chemoresistance in triple negative breast cancer (TNBC) poses a significant challenge in effective treatment, necessitating the exploration of novel therapeutic strategies. This study evaluates the efficacy of napabucasin, a potent STAT3 inhibitor, in two paclitaxel-resistant TNBC cell models (MD-MBA-231-r and BT-549-r). We observed that napabucasin significantly reduced cell viability and colony formation in a dose-dependent manner. Combination index analysis revealed synergistic interactions between napabucasin and paclitaxel, suggesting enhanced cytotoxic effects when used in combination. Mechanistically, napabucasin inhibited STAT3 signaling and impaired mitochondrial function, as evidenced by decreased phosphorylated STAT3 levels, reduced mitochondrial complex I activity, lower oxygen consumption rate and diminished ATP levels. Further analysis indicated that paclitaxel-resistant cells exhibit higher mitochondrial biogenesis and function compared to their sensitive counterparts, with elevated expression of mitochondrial genes and biogenesis regulators, and increased levels of mitochondrial respiration. In vivo, napabucasin significantly inhibited tumor growth in paclitaxel-resistant TNBC xenograft models and reduced the expression of proliferation marker Ki67 and phosphorylation of STAT3. These findings demonstrate that napabucasin effectively targets paclitaxel-resistant TNBC cells by impairing mitochondrial function and inhibiting key signaling pathways, providing a strong rationale for its further clinical investigation as a therapeutic agent to overcome chemoresistance in TBNC.