Targeting drug-tolerant persister cells to overcome resistance in HER2-positive gastric cancer.

Gastric cancer (GC) ranks as the fifth most common cancer worldwide, posing a significant global health challenge. Approximately 20 % of GC cases overexpress the human epidermal growth factor receptor 2 (HER2), a feature associated with poorer prognosis. Since the landmark Trastuzumab for Gastric Cancer (ToGA) trial, trastuzumab has become the only FDA-approved first-line therapy for HER2-positive GC. Nevertheless, nearly half of these patients exhibit either primary resistance or early relapse despite trastuzumab therapy, underscoring the urgent need for strategies beyond HER2 blockade. Drug-tolerant persister (DTP) cells are a quiescent or slowly proliferating subset of tumor cells that withstand therapy via reversible, non-genetic mechanisms. Targeting DTP cells could prevent tumor recurrence and enhance the efficacy of HER2-directed treatments. In this review, we first summarize current HER2-targeted therapies and their resistance mechanisms in GC. We then integrate emerging insights from other malignancies on DTP biology and propose potential strategies to eradicate DTP cells in HER2-positive GC. By highlighting these novel therapeutic angles, we suggest new avenues for combination regimens and biomarker development aim to improve outcomes for patients with HER2-positive GC.