It has been confirmed that HER-2 has the most outstanding clinical significance in advanced GC. However, HER-2 targeted treatment for advanced GC remains challenging due to high heterogeneity and subsequent resistance caused by prolonged medication. Although many new HER-2-targeted agents (e.g., ADCs, TKIs, bispecific antibodies, vaccines, and immunocheckpoint inhibitors) have been developed to resolve the resistance to existing HER2-targeted drugs in breast cancer and related clinical research is actively investigated in GC. The treatment of HER2-positive GC remains elusive, in addition to trastuzumab. Resistance to anti-HER-2 treatment can be overcome by jointly blocking other targets. Trastuzumab plus palbociclib (a CDK4/6 inhibitor) has been determinated to exhibit promising survival outcomes in patients with HER2-positive breast cancer (BC) [25, 26]. Whether co-treatment with trastuzumab and inhibitors of other targetes (Akt, IGF1R, PD-1, et al.) can yield the possible results is still unclear.
Compared with the new drugs under research, the benefits of functional repositioning of marketed drugs include known pharmaceutical, pharmacokinetic, and toxicological effects, short research and development cycles, etc. The Phase II clinical study of trastuzumab in combination with metformin as neoadjuvant therapy for HER2-positive breast cancer has been conducted[27]. Here, we first revealed that thioridazine restores trastuzumab sensitivity in GC. The antipsychotic drug thioridazine was first discovered as a phenothiazine-type piperidine drug. Because of its good antipsychotic effect and few extrapyramidal reactions, it has been widely used. Clinical applications of thioridazine are limited mainly by the change of electrocardiogram. In contrast, serious arrhythmias (about 1.94%) are usually caused by organic heart disease or low potassium levels. In our research, each mouse (body weight is about 20 g) received a dose of 25 mg/kg/day of thioridazine. Comparing human and animal body surface area equivalent dose ratios, the calculated dose for humans (60 kg body weight) was about 125 mg/day, the lower dose of thioridazine recommended clinically. There is evidence that thioridazine is tolerable in patients with trastuzumab-resistant gastric cancer without underlying heart disease. Due to its good performance in treating tumors and reversing drug resistance of tuberculosis, thioridazine has recently been reemphasized for its efficacy. In 2013, through high-throughput screening, Sachs et al. found that thioridazine can induce the differentiation of acute myeloid leukemia (AML) cells and breast cancer CSC, significantly enhance the sensitivity of doxorubicin, inhibit tumor proliferation without affecting the function of normal hematopoietic stem cells [28]. Since then, more and more studies have shown that thioridazine can inhibit the expression of multidrug resistance protein P-gp and enhance the sensitivity of chemotherapy drugs to glioblastoma [29]. In addition to increasing ROS and DNA damage, thioridazine can induce autophagy and apoptosis in ovarian cancer cells [30]. It reduces ovarian cancer angiogenesis by inhibiting VEGFR-2, PI3K, and mTOR signaling [31]. In this study, We first revealed that thioridazine could inhibit glycolysis, proving that thioridazine targets Skp2. The precise mechanism of thioridazine regulating the expression of Skp2 needs further analysis. The anti-tumor mechanism of thioridazine is believed to selectively block dopamine receptor D2 mediated signal transduction. Several studies have discovered that the dopamine receptor D2 is overexpressed on the surface of gastric cancer and pancreatic cancer, which is associated with poor prognoses [32]. Whether the expression and activation of dopamine receptor D2 are related to trastuzumab resistance and Skp2 expression may be related to it. We will further explore the relevant research.
Collectively, this study illustrates that thioridazine inhibits glycolysis by downregulating Skp2 expression in trastuzumab-resistance GC cells. Therefore, the combined modality approach with lapatinib and thioridazine may improve the outcome of advanced HER2-positive GC patients.