Published online Dec 7, 2023. doi: 10.3748/wjg.v29.i45.5974
Peer-review started: September 17, 2023
First decision: October 8, 2023
Revised: October 19, 2023
Accepted: November 17, 2023
Article in press: November 17, 2023
Published online: December 7, 2023
Processing time: 74 Days and 14.9 Hours
Trastuzumab constitutes the fundamental component of initial therapy for patients with advanced human epidermal growth factor receptor 2 (HER-2)-positive gastric cancer (GC). However, the efficacy of this treatment is hindered by substantial challenges associated with both primary and acquired drug resistance. While S-phase kinase associated protein 2 (Skp2) overexpression has been implicated in the malignant progression of GC, its role in regulating trastuzumab resistance in this context remains uncertain. Despite the numerous studies investigating Skp2 inhibitors among small molecule compounds and natural products, there has been a lack of successful commercialization of drugs specifically targeting Skp2.
To discover a Skp2 blocker among currently available medications and develop a therapeutic strategy for HER2-positive GC patients who have experienced progression following trastuzumab-based treatment.
Skp2 exogenous overexpression plasmids and small interfering RNA vectors were utilized to investigate the correlation between Skp2 expression and trastuzumab resistance in GC cells. Q-PCR, western blot, and immunohistochemical analyses were conducted to evaluate the regulatory effect of thioridazine on Skp2 expression. A cell counting kit-8 assay, flow cytometry, a amplex red glucose/glucose oxidase assay kit, and a lactate assay kit were utilized to measure the proliferation, apoptosis, and glycolytic activity of GC cells in vitro. A xenograft model established with human GC in nude mice was used to assess thioridazine's effectiveness in vivo.
The expression of Skp2 exhibited a negative correlation with the sensitivity of HER2-positive GC cells to trastuzumab. Thioridazine demonstrated the ability to directly bind to Skp2, resulting in a reduction in Skp2 expression at both the transcriptional and translational levels. Moreover, thioridazine effectively inhibited cell proliferation, exhibited antiapoptotic properties, and decreased the glucose uptake rate and lactate production by suppressing Skp2/protein kinase B/mammalian target of rapamycin/glucose transporter type 1 signaling pathways. The combination of thioridazine with either trastuzumab or lapatinib exhibited a more pronounced anticancer effect in vivo, surpassing the efficacy of either monotherapy.
Thioridazine demonstrates promising outcomes in preclinical GC models and offers a novel therapeutic approach for addressing trastuzumab resistance, particularly when used in conjunction with lapatinib. This compound has potential benefits for patients with Skp2-proficient tumors.
Core Tip: S-phase kinase-interacting protein 2 (Skp2) has been shown to be a reliable prognostic indicator of unfavorable outcomes for gastric cancer (GC). However, no agents specifically targeting Skp2 have been successfully developed. In this study, we proved that thioridazine restores the sensitivity of GC cells to trastuzumab both in vivo and in vitro by inhibiting Skp2-mediated glycolysis. Furthermore, the combination of thioridazine and lapatinib exhibits enhanced inhibitory effects compared with either monotherapy on the growth and survival of trastuzumab-resistant GC cells. Overall, this study suggests the potential of a thioridazine-based therapy to overcome trastuzumab resistance in human epidermal growth factor receptor 2-positive GC by targeting Skp2.