Combination treatment of PD98059 and DAPT in gastric cancer through induction of apoptosis and downregulation of WNT/β-catenin.

γ-secretase inhibitors (GSIs), the indirect inhibitors of Notch, are emerging as a new class of anticancer agents for the treatment of solid and hematological malignancies, but little is known about their effects on gastric cancer. In this study, we demonstrate that DAPT, a potent GSI, was effective to inhibit γ-secretase activity in gastric cancer (GC) cell lines that contained a fragment with approximately the size of the Notch1 intracellular domain (NICD), but was limited in their ability to induce apoptosis. However, activation of extracellular signal-regulated kinase (ERK)1/2 upon DAPT treatment was detected. Selective inhibition of ERK1/2 activation dramatically sensitized GC cells to apoptosis via downregulating β-catenin signaling in these GC cells. Notably, in a xenograft mouse tumor model, combination therapy using ERK inhibitor PD98059 plus DAPT yielded additive antitumor effects as compared with either agent alone. Taken together, these data demonstrated that γ-secretase inhibition combined with ERK1/2 inhibitor enhances cell death in GC cells partly through downregulation of WNT/β-catenin pathways.