HGF Rescues Colorectal Cancer Cells from EGFR Inhibition via MET Activation

Liska, David; Chen, Chin-Tung; Bachleitner-Hofmann, Thomas; Christensen, James G.; Weiser, Martin R.

doi:10.1158/1078-0432.ccr-10-0568

Cited by 176Colorectal Cancer Treatments and StudiesHER2/EGFR in Cancer ResearchLung Cancer Treatments and Mutations

HGF Rescues Colorectal Cancer Cells from EGFR Inhibition via MET Activation

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Liska, David, Chen, Chin-Tung, Bachleitner-Hofmann, Thomas, Christensen, James G., Weiser, Martin R.·2011·Clinical Cancer Research

DOI 10.1158/1078-0432.ccr-10-0568PMC PMC3033451

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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. Clin Cancer Res; 17(3); 472–82. ©2010 AACR.

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Only simultaneous blockade of both MET and EGFR effectively impaired tumor growth in vivo in these studies.
“In these studies, only the simultaneous blockade of both MET and EGFR effectively impaired tumor growth in vivo.”
From Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies (2014) · cites this paper as [103]
HGF-induced MET activation is a mechanism of attenuated sensitivity to cetuximab in colorectal cancer, reported by preclinical studies using colorectal cancer cell lines or spheroids.
“HGF-induced MET activation as a mechanism of attenuated sensitivity to cetuximab in CRC has been reported by preclinical studies using either CRC cell lines [103, 104] or, more recently, CRC spheroids enriched in cancer stem cells [105].”
From Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies (2014) · cites this paper as [103]
The EGF ligands HGF and TGF-α can bind to MET and then increase the phosphorylation of MET and its downstream MAPK and AKT.
“Moreover, the EGF ligands HGF and TGF-α can bind to MET and then increase the phosphorylation of MET and its downstream MAPK and AKT [121, 122].”
From Resistance to anti-EGFR therapies in metastatic colorectal cancer: underlying mechanisms and reversal strategies (2021) · cites this paper as [122]

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Authors: Liska, D., Chen, C.-T., Bachleitner-Hofmann, T., Christensen, J. G., & Weiser, M. R.
Affiliations: Memorial Sloan Kettering Cancer Center (US)
Authors' Affiliations: 1Departments of Surgery, Memorial Sloan-Kettering Cancer Center, New York; 2Department of Cancer Research, Pfizer Global Research and Development, La Jolla Laboratories, La Jolla, California
Corresponding author: Weiser, Martin R.
ORCID: Liska, David
Chen, Chin-Tung
Christensen, James G.
Weiser, Martin R.
Venue: Clinical Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2011-02-01
Volume: 17
Issue: 3
Pages: 472-482
ISSN: 1078-0432 (ISSN-L)
1557-3265
DOI: 10.1158/1078-0432.ccr-10-0568
PMC: PMC3033451
OpenAlex: W2133129337
Cited by: 176
References: 54
Citations by year: 2026: 7 · 2025: 4 · 2024: 5 · 2023: 4 · 2022: 6 · 2021: 9 · 2020: 9 · 2019: 7 · 2018: 6 · 2017: 23 · 2016: 17 · 2015: 22 · 2014: 23 · 2013: 18 · 2012: 11
FWCI: 5.37
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Clinical Cancer Research (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Cancer Institute (T32CA009501)
Topics: Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Keywords: hepatocyte growth factor, MET activation, cetuximab resistance, EGFR inhibition, colorectal cancer, mesenchymal-epithelial transition, PHA-665752, MAPK signaling, Akt signaling, cell proliferation, apoptosis, G1 cell cycle arrest, combination therapy
MeSH terms: Cetuximab, Antibodies, Monoclonal, Antineoplastic Agents, Humans, Colorectal Neoplasms, Signal Transduction, Transcriptional Activation, Hepatocyte Growth Factor, Drug Resistance, Neoplasm, Proto-Oncogene Proteins c-met, Cell Line, Tumor, Cell Proliferation, Antibodies, Monoclonal, Humanized, ErbB Receptors

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HGF Rescues Colorectal Cancer Cells from EGFR Inhibition via MET Activation

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