ArticleClinical cancer research : an official journal of the American Association for Cancer Research2011
HGF rescues colorectal cancer cells from EGFR inhibition via MET activation.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 99 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
99 citing papers in PubMed, 170 citations in OpenAlex.
- A randomized, placebo-controlled, phase 1/2 study of tivantinib (ARQ 197) in combination with irinotecan and cetuximab in patients with metastatic colorectal cancer with wild-type KRAS who have received first-line systemic therapy.International journal of cancer · 2016Trial
- Panitumumab as a radiosensitizing agent in KRAS wild-type locally advanced rectal cancer.Targeted oncology · 2015Trial
- Randomized phase Ib/II trial of rilotumumab or ganitumab with panitumumab versus panitumumab alone in patients with wild-type KRAS metastatic colorectal cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2014Trial
- Cetuximab and bevacizumab: preclinical data and phase II trial in recurrent or metastatic squamous cell carcinoma of the head and neck.Annals of oncology : official journal of the European Society for Medical Oncology · 2013Trial
- Review
- ETV4 Promotes Colorectal Cancer Progression by Reprogramming Asparagine Metabolism to Remodel the Stromal Microenvironment.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- EGFR Signaling in Colorectal Cancer: Novel Therapeutic Strategies, Predictive Biomarkers, and Counteracting Treatment Resistance.International journal of molecular sciences · 2026Review
- Research progress of small molecule protein kinase inhibitors (SMKIs) in the treatment of colorectal cancer: mechanism, application, and future prospects.Frontiers in pharmacology · 2026Review
- Prognostic significance of co-expression of c-MET and EGFR in locally advanced and metastatic gastric cancer: a retrospective cohort study.Frontiers in oncology · 2026Article
- KDM6A downregulation promotes tumor-prone cytokines expression in cancer-associated fibroblasts by activating enhancers.Cell death & disease · 2025Article
- Review
- Signaling pathways involved in colorectal cancer: pathogenesis and targeted therapy.Signal transduction and targeted therapy · 2024Review
- Bispecific antibody drug conjugates: Making 1+1>2.Acta pharmaceutica Sinica. B · 2024Review
- Nanomedicine in HNSCC therapy-a challenge to conventional therapy.Frontiers in pharmacology · 2024Review
- Review
- The differential cancer growth associated with anaesthetics in a cancer xenograft model of mice: mechanisms and implications of postoperative cancer recurrence.Cell biology and toxicology · 2023Article
- Deciphering treatment resistance in metastatic colorectal cancer: roles of drug transports, EGFR mutations, and HGF/c-MET signaling.Frontiers in pharmacology · 2023Review
- A study of gene variation in All-Journal of gastrointestinal oncology · 2022Article
- Cetuximab resistance induced by hepatocyte growth factor is overcome by MET inhibition in KRAS, NRAS, and BRAF wild-type colorectal cancers.Journal of cancer research and clinical oncology · 2022Article
- Promotion or remission: a role of noncoding RNAs in colorectal cancer resistance to anti-EGFR therapy.Cell communication and signaling : CCS · 2022Review
39 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
purposeCetuximab, 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
designDiFi, 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.
resultsEGFR 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.
conclusionsHGF-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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.