Targeting lactate with a GLUT1 inhibitor reverses PARP inhibitor resistance in ovarian cancer.

The widespread application of PARP inhibitors (PARPis) in epithelial ovarian cancer has led to the emergence of therapy resistance as a critical clinical challenge. To investigate the underlying mechanisms, we perform RNA sequencing of paired patient samples obtained before and after PARPi treatment, revealing a significant upregulation of glycolytic activity following therapy. Olaparib-resistant OVCAR8 and A2780 cells are established by exposure to increasing concentrations of Olaparib, and pharmacological inhibition or knockdown of GLUT1 restores Olaparib sensitivity, with synergistic effects confirmed in patient-derived organoids and xenograft models. Mechanistically, GLUT1 suppression reduces lactate accumulation, subsequently impairing tumor proliferation and DNA repair capacity through downregulation of the DNA repair protein MRE11. These findings establish lactate as a key mediator of PARPi resistance and propose targeting lactate metabolism as a promising combination strategy to improve PARPi efficacy in advanced ovarian cancer.