Thioridazine Reverses Trastuzumab Resistance in HER2 Positive Gastric Cancer Cells Through Down-regulation of Skp2 Expression

As the only first-line targeted therapy for advanced gastric cancer (GC) with HER2-positive status, the efficacy of trastuzumab is limited by the high rates of primary and secondary resistance. The therapeutic effect of many other HER2-targeted drugs is not satisfactory in GC. Previous studies have demonstrated that overexpression of S-phase kinase-interacting protein 2 (Skp2) predicted poor prognosis of HER2-positive GC and promoted cancer cell proliferation, resistance, and glycolysis. It has been proved that trastuzumab-resistant GC cells exhibit high glycolytic activity. We found thioridazine restores the sensitivity of trastuzumab in vivo and in vitro by inhibiting Skp2 expression and glycolytic activity. Moreover, thioridazine combined with lapatinib also showed strong inhibitory effects on the growth and survival of trastuzumab-resistant GC cells. Collectively, these data introduce a thioridazine-based therapy to overcome trastuzumab resistance in GC.