EGFR tyrosine kinase inhibition induces autophagy in cancer cells

Cancer Biol Ther. 2012 Dec;13(14):1417-24. doi: 10.4161/cbt.22002. Epub 2012 Sep 6.

Abstract

The epidermal growth factor receptor (EGFR) signaling pathway is frequently dysregulated in a variety of human malignancies. As a result, agents have been developed to selectively inhibit the tyrosine kinase function of EGFR (EGFR-TKI) for cancer therapy. However, the clinical efficacy of these drugs to date has been limited by both acquired and intrinsic resistance. Macroautophagy, a process of intracellular proteolysis, has been shown to be activated in response to EGFR targeted therapy. However, the specific role of the induction of autophagy remains controversial. Here we show that autophagy is induced in a dose-dependent manner by in vitro treatment of multiple cancer cell lines with EGFR-TKI. Additionally, we find that in cells highly resistant to EGFR-TKI, autophagy is not robustly activated and that co-treatment of these cells with rapamycin, a known inducer of autophagy, can partially restore sensitivity to EGFR-TKI. Finally, we demonstrate that, in resistant cell lines, EGFR-TKI sensitivity can be further inhibited by siRNA-mediated depletion of the critical autophagy protein ATG7. Thus, our data suggests that defective autophagy may be an EGFR-TKI resistance mechanism and that activation of autophagy may be a viable strategy to augment the cytotoxic effect of EGFR-TKIs.

Publication types

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

MeSH terms

  • Antibodies, Monoclonal, Humanized / pharmacology
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Autophagy / drug effects*
  • Autophagy-Related Protein 7
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Squamous Cell / drug therapy
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cetuximab
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / metabolism
  • Erlotinib Hydrochloride
  • HeLa Cells
  • Humans
  • Lung Neoplasms / drug therapy*
  • Mouth Neoplasms / drug therapy*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Quinazolines / pharmacology
  • RNA Interference
  • RNA, Small Interfering
  • Sirolimus / pharmacology
  • Ubiquitin-Activating Enzymes / genetics

Substances

  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Quinazolines
  • RNA, Small Interfering
  • Erlotinib Hydrochloride
  • EGFR protein, human
  • ErbB Receptors
  • Protein-Tyrosine Kinases
  • Atg7 protein, human
  • Autophagy-Related Protein 7
  • Ubiquitin-Activating Enzymes
  • Cetuximab
  • Sirolimus