Receptor Ligand-Triggered Resistance to Alectinib and Its Circumvention by Hsp90 Inhibition in EML4-ALK Lung Cancer Cells

Oncotarget. 2014 Jul 15;5(13):4920-8. doi: 10.18632/oncotarget.2055.

Abstract

Alectinib is a new generation ALK inhibitor with activity against the gatekeeper L1196M mutation that showed remarkable activity in a phase I/II study with echinoderm microtubule associated protein-like 4 (EML4)--anaplastic lymphoma kinase (ALK) non-small cell lung cancer (NSCLC) patients. However, alectinib resistance may eventually develop. Here, we found that EGFR ligands and HGF, a ligand of the MET receptor, activate EGFR and MET, respectively, as alternative pathways, and thereby induce resistance to alectinib. Additionally, the heat shock protein 90 (Hsp90) inhibitor suppressed protein expression of ALK, MET, EGFR, and AKT, and thereby induced apoptosis in EML4-ALK NSCLC cells, even in the presence of EGFR ligands or HGF. These results suggest that Hsp90 inhibitors may overcome ligand-triggered resistance to new generation ALK inhibitors and may result in more successful treatment of NSCLC patients with EML4-ALK.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzoquinones / pharmacology
  • Blotting, Western
  • Carbazoles / pharmacology*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm / drug effects*
  • Epidermal Growth Factor / pharmacology
  • ErbB Receptors / metabolism
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • HSP90 Heat-Shock Proteins / metabolism
  • Hepatocyte Growth Factor / genetics
  • Hepatocyte Growth Factor / metabolism
  • Hepatocyte Growth Factor / pharmacology
  • Humans
  • Lactams, Macrocyclic / pharmacology
  • Ligands
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Mutation
  • Oncogene Proteins, Fusion / antagonists & inhibitors*
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / metabolism
  • Phosphorylation / drug effects
  • Piperidines / pharmacology*
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-met / metabolism
  • Transforming Growth Factor alpha / pharmacology
  • Triazoles / pharmacology

Substances

  • Benzoquinones
  • Carbazoles
  • EML4-ALK fusion protein, human
  • HSP90 Heat-Shock Proteins
  • Lactams, Macrocyclic
  • Ligands
  • Oncogene Proteins, Fusion
  • Piperidines
  • Protein Kinase Inhibitors
  • STA 9090
  • Transforming Growth Factor alpha
  • Triazoles
  • 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin
  • Epidermal Growth Factor
  • Hepatocyte Growth Factor
  • ErbB Receptors
  • Proto-Oncogene Proteins c-met
  • alectinib