Heterogeneity of genetic changes associated with acquired crizotinib resistance in ALK-rearranged lung cancer

J Thorac Oncol. 2013 Apr;8(4):415-22. doi: 10.1097/JTO.0b013e318283dcc0.

Abstract

Background: Anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) is markedly sensitive to the ALK inhibitor crizotinib. However, acquired resistance to crizotinib is inevitable through several mechanisms. Therefore, this study was conducted to identify genetic alterations associated with crizotinib resistance.

Methods: Tumor samples were derived from seven ALK-positive NSCLC patients who showed acquired resistance to crizotinib, and these patients were analyzed for ALK, EGFR, and KRAS mutations and ALK and EGFR gene amplifications. In vitro cytotoxicity of crizotinib and ALK downstream signals were compared between crizotinib-naive and -resistant NSCLC cells.

Results: After a median duration of 6 months (range, 4-12 months), seven ALK-positive NSCLC patients developed acquired resistance to crizotinib. Three patients harbored secondary ALK mutations, including one patient with both mutations: L1196M (n = 2) and G1269A (n = 2). Of note, one patient displayed ALK gene copy number gain (4.1-fold increase compared with the pre-crizotinib specimen) and EGFR L858R mutation with high polysomy. The amphiregulin concentration was high in the supernatant fluid from five patients with malignant pleural effusion (116.4-18934.0 pg/ml). SNU-2535 cells derived from a patient who harbored the G1269 mutation were resistant to crizotinib treatment similar to H3122 CR1 cells. L1196M and G1269A mutant clones were less sensitive to crizotinib and ALK downstream signals were ineffectively suppressed in these clones.

Conclusions: Genetic changes associated with crizotinib resistance are heterogeneous in ALK-rearranged NSCLC patients who respond to crizotinib and subsequently develop resistance.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / genetics*
  • Adenocarcinoma / mortality
  • Adult
  • Anaplastic Lymphoma Kinase
  • Apoptosis
  • Biomarkers, Tumor / genetics*
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / mortality
  • Cell Proliferation
  • Crizotinib
  • DNA, Neoplasm / genetics
  • Drug Resistance, Neoplasm / genetics*
  • ErbB Receptors / genetics
  • Female
  • Gene Rearrangement*
  • Humans
  • In Situ Hybridization, Fluorescence
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / mortality
  • Lymph Nodes / metabolism
  • Lymph Nodes / pathology
  • Male
  • Membrane Proteins / genetics
  • Microfilament Proteins / genetics
  • Middle Aged
  • Mutation / genetics
  • Neoplasm Grading
  • Neoplasm Staging
  • Prognosis
  • Protein Kinase Inhibitors / pharmacology
  • Pyrazoles / pharmacology*
  • Pyridines / pharmacology*
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Survival Rate
  • Tumor Cells, Cultured

Substances

  • Biomarkers, Tumor
  • DNA, Neoplasm
  • KRAP protein, human
  • Membrane Proteins
  • Microfilament Proteins
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyridines
  • Crizotinib
  • ALK protein, human
  • Anaplastic Lymphoma Kinase
  • EGFR protein, human
  • ErbB Receptors
  • Receptor Protein-Tyrosine Kinases