HGF rescues colorectal cancer cells from EGFR inhibition via MET activation Journal Article
| Authors: | Liska, D.; Chen, C. T.; Bachleitner-Hofmann, T.; Christensen, J. G.; Weiser, M. R. |
| Article Title: | HGF rescues colorectal cancer cells from EGFR inhibition via MET activation |
| Abstract: | Purpose: Cetuximab, an antibody targeting the epidermal growth factor receptor (EGFR), is active in colorectal cancer (CRC). However, response rates range from only 10% to 20%. Here, we investigate hepatocyte growth factor (HGF)-dependent mesenchymal-epithelial transition factor (MET) activation as a mediator of cetuximab resistance through signal diversification in CRC cell lines. Experimental Design: DiFi, GEO, and LIM1215 cells were treated with varying concentrations and combinations of EGF, HGF, cetuximab, and PHA-665752 (a highly specific MET kinase inhibitor). Biological end points included proliferation, cell cycle arrest, and apoptosis. Proliferation was measured using WST-1 assays and synergy investigated via isobolograms. Expression and signaling were examined using immunoblotting. Results: EGFR and MET are coexpressed in these CRC cell lines, and dual receptor activation synergistically increased proliferation. Cetuximab inhibited cell growth by 60%-80% with an associated dephosphorylation of EGFR, MAPK, and/or AKT. Addition of HGF to cetuximab-treated cells phosphorylated MET, but not EGFR or ErbB3, restimulated the MAPK and AKT pathways, restored cell proliferation, and rescued cells from G1 arrest and apoptosis. Importantly, this effect could be abrogated by inhibiting MET activation with PHA-665752 or by downregulating MET expression with RNAi. Conclusions: HGF-induced MET activation is a novel mechanism of cetuximab resistance in CRC. Inhibition of the HGF-MET pathway may improve response to EGFR inhibitors in CRC, and combination therapy should be further investigated. ©2010 AACR. |
| Journal Title: | Clinical Cancer Research |
| Volume: | 17 |
| Issue: | 3 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2011-02-01 |
| Start Page: | 472 |
| End Page: | 482 |
| Language: | English |
| DOI: | 10.1158/1078-0432.ccr-10-0568 |
| PROVIDER: | scopus |
| PMCID: | PMC3033451 |
| PUBMED: | 21098338 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 4 March 2011" - "CODEN: CCREF" - "Source: Scopus" |
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
Related MSK Work