MMP7 Induces T-DM1 Resistance and Leads to The Poor Prognosis of Gastric Adenocarcinoma via a DKK1-Dependent Manner.

In this study, we identified MMP7 as one of the most up-regulated genes in T-DM1 resistant NCI-N87 gastric adenocarcinoma cells compared to matched naïve cell lines. Next, we established T-DM1 resistant NCI-N87 cell lines by exposed to T-DM1 in vitro while qPCR and Western blot showed elevated expression of MMP7 in T-DM1 resistant NCI-N87 cells. Moreover, exogenous overexpression of MMP7 promotes T-DM1 resistance and tumor growth in NCI-N87 cell lines while MMP7 knock-down enhanced sensitivity to T-DM1 in T-DM1 resistant NCI-N87 cell lines established previously. Clinically, MMP7 was found to be enriched in high WHO grade gastric adenocarcinoma samples and implies poor outcomes for these patients. Mechanically, we identified DKK1 as one of the most correlated genes to MMP7 in gastric adenocarcinoma and knock-down of DKK1 or inhibition of Wnt/β-catenin pathway led to a decreased expression of MMP7 and resistance to T-DM1. Altogether, DKK1 and Wnt/β-catenin-dependent activation of MMP7 induces T-DM1 resistance and leads to the poor prognosis of gastric adenocarcinoma, which might be a novel potential therapeutical target for T-DM1 resistant gastric adenocarcinoma.