MET activation mediates resistance to lapatinib inhibition of HER2-amplified gastric cancer cells Journal Article
| Authors: | Chen, C. T.; Kim, H.; Liska, D.; Gao, S.; Christensen, J. G.; Weiser, M. R. |
| Article Title: | MET activation mediates resistance to lapatinib inhibition of HER2-amplified gastric cancer cells |
| Abstract: | HER2 amplification is found in more than 15% of gastric cancers and is associated with poor clinical outcome. Lapatinib, a dual HER2 and epidermal growth factor receptor (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 gastric cancer cells. A panel of gastric cancer cell lines was 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 extracellular signal-regulated kinase was inhibited by lapatinib and presumably led to cell-cycle arrest as observed with flow cytometry. Hepatocyte growth factor (HGF) activation of MET receptors rescued cells from lapatinib-induced growth inhibition by restimulating the downstream pathways and restoring normal cell-cycle progression. This rescue effect could be abrogated by inhibiting MET with PHA-665752 (a highly specific MET inhibitor) or downregulating MET expression with short interfering RNA. 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 gastric cancer cells. In conclusion, HGF/MET-mediated resistance to lapatinib is a novel mechanism of resistance to HER2-targeted agents in gastric cancer cells. Development of inhibitors targeting multiple receptors or common downstream signaling proteins merits further investigation. ©2012 AACR. |
| Journal Title: | Molecular Cancer Therapeutics |
| Volume: | 11 |
| Issue: | 3 |
| ISSN: | 1535-7163 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2012-03-01 |
| Start Page: | 660 |
| End Page: | 669 |
| Language: | English |
| DOI: | 10.1158/1535-7163.mct-11-0754 |
| PROVIDER: | scopus |
| PUBMED: | 22238368 |
| PMCID: | PMC4209288 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 1 May 2012" - "CODEN: MCTOC" - "Source: Scopus" |
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