Cotargeting EGFR and autophagy signaling: A novel therapeutic strategy for non-small-cell lung cancer

Abstract

Epidermal growth factor receptor (EGFR) somatic mutations are found in the majority of non-small-cell lung cancers (NSCLCs) and patients with NSCLC who harbor EGFR mutations have been shown to exhibit increased sensitivity to the small-molecule EGFR-tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. However, the majority of tumors develop acquired resistance to EGFR-TKIs after a median of 10-16 months, which limits the clinical efficacy of these drugs. Autophagy, an important homeostatic cellular recycling mechanism, has emerged as a potential target for the acquired resistance phenotype. Recently, several studies demonstrated that autophagy may be induced in a dose-dependent manner by treatment of multiple cancer cell lines with EGFR-TKIs in vitro. Furthermore, it was recently reported that autophagy, as a cytoprotective response, may be activated by EGFR-TKIs in lung cancer cells and that the inhibition of autophagy enhanced the cytotoxic effect of EGFR-TKIs. In this review, we aimed to focus on the association between resistance to EGFR-TKIs and autophagy, and assess whether autophagy inhibition represents a promising approach to improve the efficacy of EGFR-TKIs in the treatment of NSCLC patients.

Keywords: autophagy; epidermal growth factor receptor; non-small-cell lung cancer; resistance.

Figure 1.

Plasma membrane-bound epidermal growth factor receptor (EGFR) and autophagy signaling network. Following ligand binding, EGFR is activated via phosphorylation. Phosphorylated EGFR subsequently activates the intrinsic tyrosine kinase activity of the receptor and triggers downstream signaling cascades. The major downstream pathways of EGFR include Ras/Raf/MEK/ERK/MAPK, JAK/STAT, PI3K/AKT/mTOR, NCK-PAK-JNK and PLC-PAG-PKC. All these signals exert a strong stimulatory effect on autophagy.

Figure 2.

Association between autophagy and acquired epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) resistance. Cytoplasmic EGFR contributes to autophagic regulation through its downstream signaling and EGFR mitochondrial translocation modulated by autophagy may be critical for cell survival in certain types of cancer cells. Furthermore, tumor susceptibility gene 101 (Tsg101), HIF-1α, Bcl-2 and miR-221/222 are also involved in the regulation of EGFR and autophagy. All these factors may contribute to the resistance to EGFR-TKIs in patients with non-small cell lung cancer.