Overcoming EMT-associated resistance to anti-cancer drugs via Src/FAK pathway inhibition

Oncotarget. 2014 Sep 15;5(17):7328-41. doi: 10.18632/oncotarget.2397.


Epithelial to mesenchymal transition (EMT) is a key process in embryonic development and has been associated with cancer metastasis and drug resistance. For example, in EGFR mutated non-small cell lung cancers (NSCLC), EMT has been associated with acquired resistance to the EGFR inhibitor erlotinib. Moreover, "EGFR-addicted" cancer cell lines induced to undergo EMT become erlotinib-resistant in vitro. To identify potential therapeutic vulnerabilities specifically within these mesenchymal, erlotinib-resistant cells, we performed a small molecule screen of ~200 established anti-cancer agents using the EGFR mutant NSCLC HCC827 cell line and a corresponding mesenchymal derivative line. The mesenchymal cells were more resistant to most tested agents; however, a small number of agents showed selective growth inhibitory activity against the mesenchymal cells, with the most potent being the Abl/Src inhibitor, dasatinib. Analysis of the tyrosine phospho-proteome revealed several Src/FAK pathway kinases that were differentially phosphorylated in the mesenchymal cells, and RNAi depletion of the core Src/FAK pathway components in these mesenchymal cells caused apoptosis. These findings reveal a novel role for Src/FAK pathway kinases in drug resistance and identify dasatinib as a potential therapeutic for treatment of erlotinib resistance associated with EMT.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Carcinoma, Non-Small-Cell Lung / metabolism*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Dasatinib
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / physiology*
  • Epithelial-Mesenchymal Transition / drug effects
  • Epithelial-Mesenchymal Transition / physiology*
  • ErbB Receptors / genetics
  • Erlotinib Hydrochloride
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Focal Adhesion Kinase 1 / metabolism*
  • Genes, erbB-1
  • Humans
  • Immunoblotting
  • Lung Neoplasms / metabolism*
  • Mice
  • Mice, Nude
  • Mutation
  • Pyrimidines / pharmacology
  • Quinazolines / pharmacology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Thiazoles / pharmacology
  • Xenograft Model Antitumor Assays
  • src-Family Kinases / metabolism*


  • Antineoplastic Agents
  • Pyrimidines
  • Quinazolines
  • Thiazoles
  • Erlotinib Hydrochloride
  • EGFR protein, human
  • ErbB Receptors
  • Focal Adhesion Kinase 1
  • PTK2 protein, human
  • src-Family Kinases
  • Dasatinib