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Thioridazine reverses trastuzumab resistance in gastric cancer by inhibiting S-phase kinase associated protein 2-mediated aerobic glycolysis

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE272591 | GEO | 2024/08/30

REPOSITORIES: GEO

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Project description:Background: Resistance to trastuzumab remains a common challenge to HER-2 positive breast cancer. Up until now, the underlying mechanism of trastuzumab resistance is still unclear. tRNA-derived small non-coding RNAs (tDRs), a new class of small non-coding RNA (sncRNAs), have been observed to play an important role in cancer progression. However, the relationship between tDRs and trastuzumab resistance is still unknown. Methods: We detected the levels of tDRs expression in normal breast epithelial cell lines, trastuzumab-sensitive and -resistant breast cancer cell lines using high-throughput sequencing. qRT-PCR was conducted to validate the differentially expressed tDRs in serums from trastuzumab-sensitive and -resistant patients. A receiver operating characteristic (ROC) curve analysis was performed to evaluate the power of specific tDRs. Progression-free survival (PFS) was analyzed using Cox-regression. Furthermore, Gene Ontology (GO) and pathway analyses indicated the potential mechanism underlying tDR-mediated trastuzumab resistance. Results: Our sequence results showed that tDRs were differentially expressed in the HBL-100, SKBR3, and JIMT-1 cell lines. tDR-1960 and tDR-1969 were found significantly upregulated in trastuzumab-resistant patients compared to sensitive individuals, and the ROC analysis showed that tDR-1960 and tDR-1969 were correlated with trastuzumab resistance. In a multivariate analysis, higher levels of tDR-1960 and tDR-1969 expression were associated with signiﬁcantly shorter PFS in patients with metastatic HER-2 positive breast cancer. Additionally, the GO analysis indicated that tDR-1960 and tDR-1969 were mainly involved in the cellular response to drug, which may partially explain the molecular mechanism underlying trastuzumab resistance in HER-2 positive breast cancer. Conclusion: we comprehensively analyzed tDRs in trastuzumab-sensitive and -resistant breast cancer. Our results suggest that tDR-1960 and tDR-1969 play important roles in trastuzumab resistance. Patients with high levels of tDR-1960 and tDR-1969 expression benefitted less from trastuzumab-based therapy than those that express lower-levels of these tDRs. tDR-1960 and tDR-1969 may be potential biomarkers and intervention targets in the clinical treatment of trastuzumab-resistant breast cancer.

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Thioridazine reverses trastuzumab resistance in gastric cancer by inhibiting S-phase kinase associated protein 2-mediated aerobic glycolysis

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