Combination of duligotuzumab, anti HER3 antibody or taselisib, PI3K INhibitor with trastuzumab shows synergetic antitumoral activity in HER2 positive gastric cancer cells

Abstract

Introduction: The anti-HER2 monoclonal antibody trastuzumab is central to the treatment of HER2-positive gastric cancer (GC); however, its responses are limited due to some poorly understood mechanisms of resistance. The aim of this study was to asses the antitumortal activity of Duligotuzumab, an anti HER3 antibody or Taselisib, a Pi3k inhibitor combined with Trastuzumab in a panel of HER2 positive human gastric cancer cell lines (GCG), to improve anti HER2 treatment efficacy. Methods: We evaluated in vitro the effect of Duligotuzumab, Taselisib and Trastuzumabin single agent and in combination treatments in HER2-positive GCG (NCI-N87, KATOIII, OE19) and in negative HER2 GCC (MKN28), throughproliferation, migration and apoptosis assays. We also investigated the effect of combined treatment on downstream intracellular signaling, by western blot analysis. Results: After establishing, through a dose response curve, the IC50 for each drug used (≈ 0.5 µM), a significant synergistic effect of Duligotuzumab, Taselisib and Trastuzumab treatments in HER2-positive GCG was observed by reduction of proliferation and migration in KATOIII, OE19 and N87 cell lines; the same effect was found analyzing the apoptotic rate. At cellular level, in particular in KATOIII and OE19 cell lines, the combined treatment with Duligotuzumab or Taselisib plusTrastuzumabcompletely inhibited the activation of proteins downstream of HER3, PI3K and MAPK pathways. Conclusions: Targeting both HER2 and HER3 or HER2 and PI3K with the combination of anti-HE3 antibody or pi3k inhibitor with Trastuzumab may result in an improved treatment effects on HER2-positive GCG. These important findings can be utilized to facilitate the design of future clinical trials.