Activated MET acts as a salvage signal after treatment with alectinib, a selective ALK inhibitor, in ALK-positive non-small cell lung cancer

Int J Oncol. 2015 Mar;46(3):1025-30. doi: 10.3892/ijo.2014.2797. Epub 2014 Dec 15.


Non-small cell lung cancer (NSCLC) carrying echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangements is hypersensitive to ALK inhibitors, including crizotinib and alectinib. Crizotinib was initially designed as a MET inhibitor, whereas alectinib is a selective ALK inhibitor. The MET signal, which is inhibited by crizotinib but not by alectinib, is dysregulated in many human cancers. However, the role of the MET signal in ALK-positive NSCLC remains unclear. In this study, we found that hepatocyte growth factor (HGF), ligand of MET, mediated the resistance to alectinib, but not to crizotinib, via the MET signal in ALK-positive NSCLC cell lines (H3122 and H2228 cell lines). In addition, alectinib activated the MET signal even in the absence of HGF and the inhibition of the MET signal enhanced the efficacy of alectinib. These findings suggest that activated MET acts as a salvage signal in ALK-positive NSCLC. This novel role of the MET signal in ALK-positive NSCLC may pave the way for further clinical trials examining MET inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaplastic Lymphoma Kinase
  • Carbazoles / pharmacology*
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Cell Line, Tumor / drug effects
  • Crizotinib
  • Drug Resistance, Neoplasm / drug effects
  • Hepatocyte Growth Factor / metabolism
  • Hepatocyte Growth Factor / pharmacology
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Piperidines / pharmacology*
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors
  • Proto-Oncogene Proteins c-met / genetics
  • Proto-Oncogene Proteins c-met / metabolism*
  • Pyrazoles / pharmacology
  • Pyridines / pharmacology
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Signal Transduction / drug effects


  • Carbazoles
  • HGF protein, human
  • Piperidines
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyridines
  • Crizotinib
  • Hepatocyte Growth Factor
  • ALK protein, human
  • Anaplastic Lymphoma Kinase
  • MET protein, human
  • Proto-Oncogene Proteins c-met
  • Receptor Protein-Tyrosine Kinases
  • alectinib