HER2 amplification is found in >15% of gastric cancers (GC), and is associated with poor clinical outcome. Lapatinib, a dual HER2 and EGFR tyrosine kinase inhibitor, has shown promising in-vitro results in treating HER2+ cancer cells. However, several studies have shown that activation of alternative receptor tyrosine kinases can mediate resistance to HER-targeted therapy. Here we investigated whether activated MET can confer resistance to lapatinib inhibition of GC cells. A panel of gastric cancer cell lines were treated with lapatinib and we observed that cell proliferation was reduced by 70% and that the degree of HER2 amplification corresponds to sensitivity to lapatinib. Immunoblotting analysis indicated that phosphorylation of HER2, EGFR, MET, AKT and ERK were inhibited by lapatinib and presumably led to cell cycle arrest as observed using flow cytometry. HGF activation of MET receptors rescued cells from lapatinib-induced growth inhibition by re-stimulating the downstream pathways and restoring normal cell cycle progression. This rescue effect could be abrogated by inhibiting MET using PHA-665752 (a highly specific MET inhibitor), or downregulating MET expression with siRNA. No synergy in growth inhibition was observed when cells were treated with a combination of lapatinib and PHA-665752. Repeat studies using insulin-like growth factor 1 and fibroblast growth factor 3 could not uniformly rescue the lapatinib treated GC cells. In conclusion, HGF/MET mediated resistance to lapatinib is a novel mechanism of resistance to HER2-targeted agents in GC cells. Development of inhibitors targeting multiple receptors or common downstream signaling proteins merits further investigation.

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