Clinical response to crizotinib and emergence of resistance in lung adenocarcinoma harboring a MET c-Cbl binding site mutation

Lung Cancer. 2020 Jan;139:165-168. doi: 10.1016/j.lungcan.2019.11.020. Epub 2019 Nov 26.


Objectives: MET c-Cbl binding site mutations constitute about 2 % of MET exon 14 alterations in lung cancer. Preclinical data suggests regarding these mutations as functional analogs of MET exon 14 skipping mutations, but clinical validation is lacking.

Results: We report the case of a patient with metastastic lung adenocarcinoma harboring a c-Cbl binding site alteration and demonstrate clinical, radiological and metabolic response to crizotinib with a PFS of 10.6 months. As escape mechanism, a typical MET resistance mutation could be identified.

Conclusion: MET c-Cbl binding site mutations should be regarded as a distinct subtype of MET exon 14 alterations. Patients with lung cancer harboring such mutations should be offered targeted therapy.

Keywords: Crizotinib; MET mutation; NSCLC; c-Cbl.

Publication types

  • Case Reports

MeSH terms

  • Adenocarcinoma of Lung / drug therapy
  • Adenocarcinoma of Lung / genetics
  • Adenocarcinoma of Lung / metabolism
  • Adenocarcinoma of Lung / pathology*
  • Aged
  • Binding Sites
  • Crizotinib / therapeutic use*
  • Drug Resistance, Neoplasm / genetics*
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology*
  • Male
  • Mutation*
  • Prognosis
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins c-cbl / genetics
  • Proto-Oncogene Proteins c-cbl / metabolism*
  • Proto-Oncogene Proteins c-met / genetics
  • Proto-Oncogene Proteins c-met / metabolism*


  • Protein Kinase Inhibitors
  • Crizotinib
  • Proto-Oncogene Proteins c-cbl
  • Proto-Oncogene Proteins c-met