The impact of the PI3K/AKT/mTOR signaling pathway on trastuzumab resistance in HER2-positive gastric cancer

Gastric cancer is a major cause of cancer-related mortality worldwide, frequently diagnosed at advanced stages due to its asymptomatic early course. HER2-positive gastric cancer represents a clinically significant subgroup, characterized by overexpression of the HER2 receptor, which promotes tumor progression and adverse clinical outcomes. Trastuzumab, a monoclonal antibody targeting HER2, has achieved substantial therapeutic advances; however, the emergence of treatment resistance remains a major limitation. Recent evidence indicates that the PI3K/Akt/mTOR signaling pathway plays a central role in mediating trastuzumab resistance, as its dysregulation enhances tumor cell survival and proliferation, angiogenesis, epithelial-to-mesenchymal transition, and evasion of apoptosis, ultimately resulting in treatment failure. This study examines the biological and clinical significance of HER2 in gastric cancer and explores the molecular mechanisms underlying PI3K/Akt/mTOR-mediated resistance to trastuzumab. Furthermore, emerging therapeutic strategies targeting these mechanisms may facilitate the development of effective, personalized treatment approaches for patients with HER2-positive gastric cancer.