Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer

Cancer Discov. 2011 Jun;1(1):78-89. doi: 10.1158/2159-8274.CD-11-0005.

Abstract

While genomically targeted therapies have improved outcomes for patients with lung adenocarcinoma, little is known about the genomic alterations which drive squamous cell lung cancer. Sanger sequencing of the tyrosine kinome identified mutations in the DDR2 kinase gene in 3.8% of squamous cell lung cancers and cell lines. Squamous lung cancer cell lines harboring DDR2 mutations were selectively killed by knock-down of DDR2 by RNAi or by treatment with the multi-targeted kinase inhibitor dasatinib. Tumors established from a DDR2 mutant cell line were sensitive to dasatinib in xenograft models. Expression of mutated DDR2 led to cellular transformation which was blocked by dasatinib. A squamous cell lung cancer patient with a response to dasatinib and erlotinib treatment harbored a DDR2 kinase domain mutation. These data suggest that gain-of-function mutations in DDR2 are important oncogenic events and are amenable to therapy with dasatinib. As dasatinib is already approved for use, these findings could be rapidly translated into clinical trials.

Significance: DDR2 mutations are present in 4% of lung SCCs, and DDR2 mutations are associated with sensitivity to dasatinib. These findings provide a rationale for designing clinical trials with the FDA-approved drug dasatinib in patients with lung SCCs.

Keywords: DDR2; Squamous cell lung cancer; dasatinib; lung cancer genomics; tyrosine kinase inhibitors.

Publication types

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

MeSH terms

  • Animals
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / enzymology
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Cell Transformation, Neoplastic / drug effects
  • Cell Transformation, Neoplastic / genetics
  • Dasatinib
  • Discoidin Domain Receptors
  • Erlotinib Hydrochloride
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / enzymology
  • Lung Neoplasms / genetics*
  • Mice
  • Mice, Nude
  • Mutation
  • NIH 3T3 Cells
  • Phosphorylation / drug effects
  • Phosphorylation / genetics
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use
  • Quinazolines / pharmacology
  • Quinazolines / therapeutic use
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Receptors, Mitogen / genetics*
  • Thiazoles / pharmacology
  • Thiazoles / therapeutic use
  • src-Family Kinases / genetics

Substances

  • Protein Kinase Inhibitors
  • Pyrimidines
  • Quinazolines
  • Receptors, Mitogen
  • Thiazoles
  • Erlotinib Hydrochloride
  • Discoidin Domain Receptors
  • Receptor Protein-Tyrosine Kinases
  • src-Family Kinases
  • Dasatinib