MET activation confers resistance to cetuximab, and prevents HER2 and HER3 upregulation in head and neck cancer

Int J Cancer. 2019 Aug 1;145(3):748-762. doi: 10.1002/ijc.32170. Epub 2019 Feb 11.


An understanding of the mechanisms underlying acquired resistance to cetuximab is urgently needed to improve cetuximab efficacy in patients with head and neck squamous cell carcinoma (HNSCC). Here, we present a clinical observation that MET pathway activation constitutes the mechanism of acquired resistance to cetuximab in a patient with HNSCC. Specifically, RNA sequencing and mass spectrometry analysis of cetuximab-sensitive (CetuxSen ) and cetuximab-resistant (CetuxRes ) tumors indicated MET amplification and overexpression in the CetuxRes tumor compared to the CetuxSen lesion. Stimulation of MET in HNSCC cell lines was sufficient to reactivate the MAPK pathway and to confer resistance to cetuximab in vitro and in vivo. In addition to the direct role of MET in reactivation of the MAPK pathway, MET stimulation abrogates the well-known cetuximab-induced compensatory feedback loop of HER2/HER3 expression. Mechanistically, we showed that the overexpression of HER2 and HER3 following cetuximab treatment is mediated by the ETS homologous transcription factor (EHF), and is suppressed by MET/MAPK pathway activation. Collectively, our findings indicate that evaluation of MET and HER2/HER3 in response to cetuximab in HNSCC patients can provide the rationale of successive line of treatment.

Keywords: MET; cetuximab; drug resistance; head and neck cancer; signaling.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cetuximab / pharmacokinetics
  • Cetuximab / pharmacology*
  • Drug Resistance, Neoplasm
  • Enzyme Activation
  • Gene Expression
  • Head and Neck Neoplasms / drug therapy*
  • Head and Neck Neoplasms / enzymology
  • Head and Neck Neoplasms / genetics
  • Humans
  • Indoles / pharmacology
  • MAP Kinase Signaling System
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Proto-Oncogene Proteins c-met / metabolism*
  • Random Allocation
  • Receptor, ErbB-2 / antagonists & inhibitors
  • Receptor, ErbB-2 / biosynthesis
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / metabolism*
  • Receptor, ErbB-3 / antagonists & inhibitors
  • Receptor, ErbB-3 / biosynthesis
  • Receptor, ErbB-3 / genetics
  • Receptor, ErbB-3 / metabolism*
  • Squamous Cell Carcinoma of Head and Neck / drug therapy*
  • Squamous Cell Carcinoma of Head and Neck / enzymology
  • Squamous Cell Carcinoma of Head and Neck / genetics
  • Sulfones / pharmacology
  • Up-Regulation
  • Xenograft Model Antitumor Assays


  • 5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one
  • Indoles
  • Sulfones
  • ERBB2 protein, human
  • ERBB3 protein, human
  • MET protein, human
  • Proto-Oncogene Proteins c-met
  • Receptor, ErbB-2
  • Receptor, ErbB-3
  • Cetuximab