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Review
. 2019 Sep 16;11(9):1374.
doi: 10.3390/cancers11091374.

Targeting Autophagy for Overcoming Resistance to Anti-EGFR Treatments

Yoojung Kwon  1 , Misun Kim  2 , Hyun Suk Jung  3 , Youngmi Kim  4 , Dooil Jeoung  5
Affiliations
Review

Targeting Autophagy for Overcoming Resistance to Anti-EGFR Treatments

Yoojung Kwon et al. Cancers (Basel). .

Abstract

Epidermal growth factor receptor (EGFR) plays critical roles in cell proliferation, tumorigenesis, and anti-cancer drug resistance. Overexpression and somatic mutations of EGFR result in enhanced cancer cell survival. Therefore, EGFR can be a target for the development of anti-cancer therapy. Patients with cancers, including non-small cell lung cancers (NSCLC), have been shown to response to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) and anti-EGFR antibodies. However, resistance to these anti-EGFR treatments has developed. Autophagy has emerged as a potential mechanism involved in the acquired resistance to anti-EGFR treatments. Anti-EGFR treatments can induce autophagy and result in resistance to anti-EGFR treatments. Autophagy is a programmed catabolic process stimulated by various stimuli. It promotes cellular survival under these stress conditions. Under normal conditions, EGFR-activated phosphoinositide 3-kinase (PI3K)/AKT serine/threonine kinase (AKT)/mammalian target of rapamycin (mTOR) signaling inhibits autophagy while EGFR/rat sarcoma viral oncogene homolog (RAS)/mitogen-activated protein kinase kinase (MEK)/mitogen-activated protein kinase (MAPK) signaling promotes autophagy. Thus, targeting autophagy may overcome resistance to anti-EGFR treatments. Inhibitors targeting autophagy and EGFR signaling have been under development. In this review, we discuss crosstalk between EGFR signaling and autophagy. We also assess whether autophagy inhibition, along with anti-EGFR treatments, might represent a promising approach to overcome resistance to anti-EGFR treatments in various cancers. In addition, we discuss new developments concerning anti-autophagy therapeutics for overcoming resistance to anti-EGFR treatments in various cancers.

Keywords: EGFR signaling; anti-EGFR treatments; autophagy; co-targeting.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structure of the human ErbB/HER receptors. (A) Extracellular domain (ECD) of each receptor consists of four domains (I–IV). Domains I and III participate in ligand binding (except for those of HER2). Domain II participates in dimer formation. Intracellular domain (ICD) is composed of protein kinase domain (PKD) and regulatory domain (RD). HER3 does not have active kinase domain. (B) Growth factors that can bind to the ErbB/HER receptors are indicated. AR, amphiregulin; BTC, betacellulin; EGF, epidermal growth factor; EPF, extracellular protein factor; EPR, epiregulin; HB-EGF, heparin-binding epidermal growth factor-like growth factor; Nrg-1/2/3/4, neuregulin-1/2/3/4; TGF-α, transforming growth factor α. TM denotes transmembrane and JM denotes juxtamembrane segments.
Figure 2
Figure 2
Domains of EGFR and the sites of mutations. Mutations that are associated with sensitivity or resistance to EGFR-TKIs are denoted. Specific mutations in the kinase domain of EGFR are shown. TKI denotes tyrosine kinase inhibitor.
Figure 3
Figure 3
Ligand-dependent EGFR signaling pathways. (A) The proteins recruited on tyrosine-phosphorylated EGFR residues are shown. Numbers correspond to amino acids of EGFR. TM denotes transmembrane domain, TK denotes tyrosine kinase domain, and RD denotes regulatory domain. Specific mutations in the kinase domain and regulatory domain of EGFR are shown. Δ denotes deletions. (B) EGFR activates RAS/MAPK and JAK/STAT signaling pathways for cell survival. Activation of PI3K/AKT/mTOR signaling pathway leads to protein synthesis. EGFR activates Phospholipase C gamma (PLCγ), which in turn activates PKC/IKKβ/NF-κB signaling pathway.
Figure 4
Figure 4
Cross talk between EGFR signaling and autophagy. Tyrosine phosphorylation of Beclin1 by EGFR leads to homodimerization of Beclin1 and binding of inhibitors of autophagy such as rubicon and B-cell lymphoma 2 (Bcl-2) to Beclin1 to decrease autophagic activity. EGFR-PI3K/AKT/mTOR signaling can inhibit autophagy by inhibiting phosphorylation of Beclin1 on serine residues. EGFR-RAF/MEK/extracellular signal-regulated kinases (ERK) signaling can activate autophagy by increasing serine phosphorylation of Beclin1. Beclin1-containing class III PI3 kinase complex initiates formation of autophagosomes. Autophagophore formation requires ATG12-ATG5-ATG16L1 conjugate. ATG4 cleaves microtubule-associated protein 1-light chain 3 (LC3) at the C-terminus to result in formation of LC3I, which is conjugated with phosphatidyl ethanolamine (PE) to become LC3II. LC3II is present on autophagosomes. Autophagosome fuses with lysosome to form autolysosome where intracellular contents are degraded and are recycled.
Figure 5
Figure 5
Antibody-dependent cell-mediated cytotoxicity mediates cytotoxic effect of cetuximab. (A) Upon binding of EGF, EGFR activates JAK2, which in turn leads to the activation of STAT3. STAT3 increases expression of immune suppressive cytokines, such as IL-6, IL-10, and TGF-β. IL-6, in autocrine fashion, binds to and activates IL-6 receptor. This binding activates STAT3. EGFR signaling activates regulatory T cells (Treg cells). Activated Treg cells suppress cytotoxic effects of natural killer cells (NK cells) and CD8+ T cells. IL-10 and TGF-β can also activate Treg cells. (B) Cetuximab-activated NK cells display cytotoxic effects against cancer cells by perforin and granzyme B (left). Cetuximab-activated NK cells interact with cancer cells through natural killer group 2 member D (NKG2D)- MHC class I chain-related gene A (MIC-A) binding. This interaction induces dendritic cell (DC) maturation by increasing expression levels of transporter 1 ATP-binding cassette sub-family B(TAP-1)/transporter 2 ATP-binding cassette sub-family B (TAP-2) and human leukocyte antigen I (HLA I) via interferon (IFN)-γ. DC maturation enhances cytolytic T lymphocytic activity towards cancer cells (right).
Figure 6
Figure 6
Anti-cancer drugs targeting EGFR signaling and autophagy. (A) Anti-EGFR monoclonal antibodies (mAbs) targeting EGFR include cetuximab, panitumumab, zalutumumab, and imgatuzumab. These mAbs bind to extracellular domain of EGFR and inhibit binding of ligands to EGFR. EGFR-TKI such as erlotinib targets intracellular tyrosine kinase domain to inhibit autophosphorylation of EGFR. Buparlisib and Alpelisib target PI3 Kinase. Everolimus targets mTOR activity and PI3K signaling. SCH772984 targets ERK activity. (B) Wortmannin, 3-methyladenine (3-MA), and LY294002 inhibit VPS34 complex formation. Spautin-1 promotes its degradation. Hydroxychloroquine (HQ), chloroquine (CQ), and bafilomycin A1 inhibit fusion of autophagosome with lysosome.
Figure 7
Figure 7
Targeting autophagy may overcome resistance to anti-EGFR treatments. (A) Resistance to anti-EGFR treatments develops from mutations and amplifications, phenotypic changes, and autophagy. (B) Anti-EGFR treatments such as anti-EGFR mAbs and EGFR-TKIs induce protective autophagy in cancer cells, which confers resistance to these anti-EGFR treatments. Targeting both EGFR and autophagy may overcome resistance to anti-EGFR treatments. Anti-autophagy therapy includes miRNA-mimic, miRNA-inhibitors, peptides, and small interfering RNAs (siRNAs).
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