Hedgehog inhibitors exert anti-proliferation effects and synergistically interact with trastuzumab in HER2-positive gastric cancer models.

BACKGROUND: Gastric cancer (GC) remains a significant health concern with limited therapeutic options. While trastuzumab, a Human Epidermal Growth Factor Receptor 2 (HER2)-targeting antibody, has shown efficacy in HER2-positive GC, its therapeutic response is moderate. Hedgehog (Hh) signalling plays a critical role in the progression of GC. METHODS: We evaluated the sensitivity of various GC cell lines to trastuzumab. The HER2-positive HGC-27 cell line was identified as the most sensitive. In addition, the effects of two Hedgehog inhibitors, vismodegib and cyclopamine, were assessed on cell growth by monitoring SMO expression. Both in vitro and in vivo assays were conducted to explore the combination of Hh inhibitors and trastuzumab. RESULTS: Both vismodegib and cyclopamine exerted anti-proliferative effects, and synergistically enhanced the anti-tumour activity of trastuzumab in HER2-positive GC models. Mechanistically, Hh inhibitors inhibited the AKT/mTOR signalling pathway through Smoothened (SMO) depletion, contributing to their anti-growth effects. INTERPRETATION: This study highlights the potential of combining Hh inhibitors with trastuzumab as a therapeutic strategy for HER2-positive GC by targeting the AKT/mTOR pathway.