EGFR tyrosine kinase inhibition induces autophagy in cancer cells

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.

Keywords: :

• EGFR
• TKI
• autophagy
• epidermal
• erlotinib
• gefitinib
• rapamycin

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

These studies were supported by grants 57006715 (C.F.) from the Howard Hughes Medical Institute, 5P50CA097190 and 2R01CA098372 (J.G.) from the National Institutes of Health, CRP-08–229–01 (J.G.) from the American Cancer Society, and CDA-2–057–10S (U.D.) from the United States Department of Veteran’s Affairs. The ideas in this article do not represent the views of the Department of Veteran's Affairs.