Work

BIRC3 induces the phosphoinositide 3-kinase-Akt pathway activation to promote trastuzumab resistance in human epidermal growth factor receptor 2-positive gastric cancer

Year: 2024

Type: article

Abstract: BACKGROUND Trastuzumab-targeted therapy is currently the standard of care for advanced human epidermal growth factor receptor 2 (HER2)-positive gastric cancer. However, the emergence of resistance to trastuzumab poses significant challenges. AIM To identify the key genes associated with trastuzumab resistance. These results provide a basis for the development of interventions to address drug resistance and improve patient outcomes. METHODS High-throughput sequencing and bioinformatics were used to identify the differentially expressed pivotal gene BIRC3 and delineate its potential function and pathway regulation. Tumor samples were collected from patients with HER2-positive gastric cancer to evaluate the correlation between BIRC3 expression and trastuzumab resistance. We established gastric cancer cell lines with both highly expressed and suppressed levels of BIRC3 , followed by comprehensive in vitro and in vivo experiments to confirm the involvement of BIRC3 in trastuzumab resistance and to elucidate its underlying mechanisms. RESULTS In patients with HER2-positive gastric cancer, there is a significant correlation between elevated BIRC3 expression in tumor tissues and higher T stage, tumor node metastasis stage, as well as poor overall survival and progression-free survival. BIRC3 is highly expressed in trastuzumab-resistant gastric cancer cell lines, where it inhibits tumor cell apoptosis and enhances trastuzumab resistance by promoting the phosphorylation and activation of the phosphoinositide 3-kinase-Akt (PI3K-AKT) pathway in HER2-positive gastric cancer cells, both in vivo and in vitro . CONCLUSION This study revealed a robust association between high BIRC3 expression and an unfavorable prognosis in patients with HER2-positive gastric cancer. Thus, the high expression of BIRC3 stimulated PI3K-AKT phosphorylation and activation, stimulating the proliferation of HER2-positive tumor cells and suppressing apoptosis, ultimately leading to trastuzumab resistance.

Source: World Journal of Gastrointestinal Oncology

DOI: 10.4251/wjgo.v16.i11.4436