期刊
CANCER BIOLOGY & THERAPY
卷 13, 期 14, 页码 1417-1424出版社
TAYLOR & FRANCIS INC
DOI: 10.4161/cbt.22002
关键词
EGFR; erlotinib; gefitinib; epidermal; autophagy; TKI; rapamycin
类别
资金
- Howard Hughes Medical Institute [57006715]
- National Institutes of Health [5P50CA097190, 2R01CA098372]
- American Cancer Society [CRP-08-229-01]
- United States Department of Veteran's Affairs [CDA-2-057-10S]
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据