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

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 and delineate its potential function and pathway regulation. Tumor samples were collected from patients with HER2-positive gastric cancer to evaluate the correlation between expression and trastuzumab resistance. We established gastric cancer cell lines with both highly expressed and suppressed levels of , followed by comprehensive and experiments to confirm the involvement of in trastuzumab resistance and to elucidate its underlying mechanisms.

RESULTS

In patients with HER2-positive gastric cancer, there is a significant correlation between elevated expression in tumor tissues and higher T stage, tumor node metastasis stage, as well as poor overall survival and progression-free survival. 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 and .

CONCLUSION

This study revealed a robust association between high expression and an unfavorable prognosis in patients with HER2-positive gastric cancer. Thus, the high expression of stimulated PI3K-AKT phosphorylation and activation, stimulating the proliferation of HER2-positive tumor cells and suppressing apoptosis, ultimately leading to trastuzumab resistance.