Epidermal growth factor receptor: Structure-function informing the design of anticancer therapeutics

doi:10.1016/j.yexcr.2018.08.009

Experimental Cell Research

Volume 371, Issue 1, 1 October 2018, Pages 1-19

https://doi.org/10.1016/j.yexcr.2018.08.009 Get rights and content

Highlights

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Analysis of progress in the structure and function of EGFR-family and ligands.
•
Discussion of EGFR-family signaling in tissue homeostasis and disease.
•
Pro-ligand processing wound healing and cancer.
•
Targeting signaling from the EGFR-family to improve cancer treatment.

Abstract

Research on the epidermal growth factor (EGF) family and the family of receptors (EGFR) has progressed rapidly in recent times. New crystal structures of the ectodomains with different ligands, the activation of the kinase domain through oligomerisation and the use of fluorescence techniques have revealed profound conformational changes on ligand binding. The control of cell signaling from the EGFR-family is complex, with heterodimerisation, ligand affinity and signaling cross-talk influencing cellular outcomes. Analysis of tissue homeostasis indicates that the control of pro-ligand processing is likely to be as important as receptor activation events. Several members of the EGFR-family are overexpressed and/or mutated in cancer cells. The perturbation of EGFR-family signaling drives the malignant phenotype of many cancers and both inhibitors and antagonists of signaling from these receptors have already produced therapeutic benefits for patients. The design of affibodies, antibodies, small molecule inhibitors and even immunotherapeutic drugs targeting the EGFR-family has yielded promising new approaches to improving outcomes for cancer patients. In this review, we describe recent discoveries which have increased our understanding of the structure and dynamics of signaling from the EGFR-family, the roles of ligand processing and receptor cross-talk. We discuss the relevance of these studies to the development of strategies for designing more effective targeted treatments for cancer patients.

Introduction

“I am both amazed and encouraged by the unpredictable scientific and clinical consequences of simply wondering what caused precocious eyelid openings in newborn mice.” – Stanley Cohen [1]

The Epidermal Growth Factor Receptor (EGFR) is a trans-membrane protein implicated in a wide range of developmental biology processes; [2], [3], [4] and human cancers including glioblastoma, non-small cell lung cancer (NSCLC), head and neck cancer and colorectal cancer [5], [6], [7], [8], [9], [10], [11], [12]. The EGFR family has four homologous members: [13], [14] EGFR, also known as ERBB1 or HER1, HER2, also known as ERBB2, HER3 or ERBB3, and HER4 or ERBB4. Each family member has an extracellular domain (ECD) with two cysteine-rich regions, a single trans-membrane, or membrane-spanning region, a juxtamembrane cytoplasmic domain, and an intracellular kinase (or pseudokinase) domain with multiple C-terminal tyrosine residues which are phosphorylated on ligand binding and receptor activation (Fig. 1) [13], [15].

This article provides a framework for understanding new structural insights into the function of the EGFR and describes how new discoveries are informing efforts to improve personalised cancer treatment. We describe the structure, function and targeting of the EGFR family, starting with the extracellular components, i.e. the ectodomains (ECD), proceeding to the transmembrane and juxtamembrane components, and finishing with the intracellular domains, including the tyrosine kinase and C-terminal domains. Some therapeutic strategies, based on our knowledge of the EGFR are considered in the context of dual-target monoclonal antibodies, [16] dual-target inhibitors, [17] ligand-targeting [18] and convection enhanced delivery [19]. The use of these agents to avoid the potential development of resistance to cancer treatment is discussed. Conformational change, [20] oligomerisation, [21] and clustering [22] of EGFR are considered as mechanisms involved in ligand-stimulated kinase activation. This update concludes with a discussion of the relevance of the models of ligand activation, EGFR signaling and recycling for the maintenance of the tumourigenic state and the potential of this information to improve outcomes for cancer patients.

Section snippets

EGFR-family

Growth factor signaling is a critical feature of tissue homeostasis. Since the discovery of Epidermal Growth Factor (EGF), [1] the EGF:EGF-receptor (EGF:EGFR) system has been at the forefront of our knowledge on the structure and function of growth factors, cytokines and cell biology. The EGF:EGFR system is regulated at many levels, the EGFR, the release of activated ligands from their precursors, the induction and activation of the enzymes which release the EGF-like ligands, the processes and

New approaches to ectodomain targeting – disrupting oligomerisation

Dimer or higher-level oligomer formation is important for EGFR activation [84]. The conditions for dimerisation of the EGFR have been studied in detail, [84] and it has been understood for some time that point mutations to either Y246 or Y251, two conserved tyrosines on the oligomerisation arm in domain II of the ECD, both abolish dimerisation and interfere with receptor activation [84], [85], [86]. One strategy to inhibit EGFR signaling is to target the dimerisation arm in the β-hairpin loop

Targeting the transmembrane and juxtamembrane domains of EGFR

The 3D-structure of the EGFR transmembrane domain (TMD) was determined by nuclear magnetic resonance (NMR) spectroscopy [114]. The TMD comprises an initial N-terminal 3–10 turn (residues 644–647) [115] followed by an α-helical region (residues 648–669). [115] Mineev and colleagues [116] studied the conformation of a fragment of the EGFR comprising the juxtamembrane domains and the transmembrane domains (i.e. residues 642–690). On either side of the membrane, the juxtamembrane domains (JMDs) at

The tyrosine kinase domain: structure, mutations, and targeting

The TKD (residues 688–979) is often mutated in cancerous tissue, e.g. L858R- and T790M-EGFR substitutions in NSCLC [138], [139], [140]. The structure of the EGFR-TKD, including 43 aa from the carboxyl-terminal tail, has been solved crystallographically, both free and with erlotinib bound [141]. These 3D-structures also reveal a putative intracellular dimerisation motif which is concentrated in the Leu⁹⁵⁵-Val⁹⁵⁶-Ile⁹⁵⁷ segment lying between the TKD and the carboxyl-terminal tail, as well as

EGFR membrane dynamics

Despite progress in our understanding of the structural biology of the EGFR family, our knowledge of the configuration of the EGFR family members on the cell surface is still incomplete. Recent single-molecule studies [174] have assisted in the investigation of membrane receptor oligomerisation: stepwise photobleaching [175], FRET [176], sub-diffraction localisation microscopy [177], and co-tracking [178]. The distribution of aggregation states for a receptor can now be interrogated at the

EGFR hetero-oligomerisation and clustering

On the cell surface all four ERBB family members are capable of forming heterodimers [192], but HER2 appears to be the preferred dimerisation partner [192]. Since HER2 has no ligand [193] and HER3 is an inactive kinase, [142] it is not surprising that only EGFR and HER4 appear to form homodimers/oligomers which contribute to downstream signaling [192], [194], [195], [196]. It is likely that signaling by HER2/3 heterodimers involves the formation of higher-order oligomers [194]. Using luciferase

EGFR signaling

Historically it has been thought that ligand-induced receptor dimerisation is the key component of EGFR signaling [211], however work done on an EGFR orthologue, the Caenorhabditis elegans LET-23 which is constitutively dimeric [212] suggests EGFR may be regulated by ligand induced allosteric changes in pre-existing receptor dimers [212]. Stimulation of the LET-23 receptor with its ligand LIN-3, appears to respond without alteration in oligomerisation status [212]. When mutational analyses were

EGFR endocytosis and recycling

Inactive receptors are internalised spontaneously, but slowly and these unligated receptors are recycled rapidly back to the cell surface [230]. However, upon ligand binding, active receptors travel through the endosomal system where signaling continues and receptors are either recycled back to the cell surface or taken up into proteolytic lysosomes [231], [232], [233]. Several process including the phosphorylation of the β2 subunit of AP-2 [234], [235], receptor ubiquitylation through the E3

EGFR crosstalk

EGFR signaling can lead to activation of other signaling systems and vice versa. Understanding these cross interactions are important for predicting the effects of regulators on tissue biology.

Earlier discussions in this review indicate that the different EGFR family members can interact directly forming multiple signaling systems: in the EGFR:HER2 both kinases are activated when ligands binds to the EGFR, similarly the EGFR:HER4 is a dual specificity receptor kinase. Although the HER2:HER3

Overcoming resistance and new therapeutic strategies based on targeting the EGFR

As discussed earlier, secondary drug resistance in NSCLC can arise from EGFR-TKD mutations e.g. EGFR-T790M during TKI therapy [164], however, there are intrinsic pathway modulations and feedback loops induced by TKIs which can also lead to drug resistance (Fig. 9). One downstream effect of the action of EGFR kinase inhibitors is the reduction of Akt activity and a consequential reduction in Ets-1 activity [275]. Reduction in Ets-1 activity will reduce the expression of the DUSP6 phosphatase a

Conclusions and future directions

We have discussed recent developments in the structure and function of the EGFR family and their ligands. These discoveries are informing improved development of EGFR targeting drugs and even improving cancer treatment. There are new agents which can disrupt the formation of EGFR oligomers, and by combining EGFR targeting agents with complimentary epitopes, profound downregulation of ligand stimulated EGFR activity can be achieved. In the transmembrane and juxtamembrane domains of the EGFR, the

Acknowledgements

This work was funded in part by the National Health and Medical Research Council through Program Grant no. 1092788. The granting agency had no direct input into this article. R.B.L. is a recipient of the Victorian Cancer Agency Mid-Career Research Fellowship (MCRF15017). R.A.M. is a recipient of a Brain Foundation research grant and a Royal Australasian College of Surgeons Research Scholarship.

Declarations of interest

None.

References (287)

S. Cohen
Origins of growth factors: NGF and EGF
J. Biol. Chem.
(2008)
S. Fujino
A comparison of epidermal growth factor receptor levels and other prognostic parameters in non-samll cell lung cancer
Eur. J. Cancer
(1996)
F. Danhier et al.
Combined anti-Galectin-1 and anti-EGFR siRNA-loaded chitosan-lipid nanocapsules decrease temozolomide resistance in glioblastoma: in vivo evaluation
Int. J. Pharm.
(2015)
H. Yamashita et al.
Oligomerization–function relationship of EGFR on living cells detected by the coiled-coil labeling and FRET microscopy
Biochim. Biophys. Acta (BBA)-Biomembr.
(2015)
A. Arkhipov
Architecture and membrane interactions of the EGF receptor
Cell
(2013)
W. Humphrey et al.
VMD: visual molecular dynamics
J. Mol. Graph.
(1996)
Y. Kokai
Synergistic interaction of p185c-neu and the EGF receptor leads to transformation of rodent fibroblasts
Cell
(1989)
K.M. Ferguson
EGF activates its receptor by removing interactions that autoinhibit ectodomain dimerization
Mol. Cell
(2003)
T.P. Garrett
Crystal structure of a truncated epidermal growth factor receptor extracellular domain bound to transforming growth factor α
Cell
(2002)
H. Ogiso et al.
Crystal structure of the complex of human epidermal growth factor and receptor extracellular domains
Cell
(2002)

I. Rebay

Specific EGF repeats of Notch mediate interactions with Delta and Serrate: implications for Notch as a multifunctional receptor

Cell

(1991)

G. Sirokmány

Epidermal growth factor-induced hydrogen peroxide production is mediated by dual oxidase 1

Free Radic. Biol. Med.

(2016)

C. Berasain et al.

Amphiregulin

Semin. Cell Dev. Biol.

(2014)

H. Schulz

Betacellulin transgenic mice develop urothelial hyperplasia and show sex-dependent reduction in urinary major urinary protein content

Exp. Mol. Pathol.

(2015)

Y. Sun

Neuregulin-1/ErbB4 signaling regulates visual cortical plasticity

Neuron

(2016)

G. Carpenter et al.

Characterization of the binding of 125-I-labeled epidermal growth factor to human fibroblasts

J. Biol. Chem.

(1975)

R. Derynck et al.

Human transforming growth factor-α: precursor structure and expression in E. coli

Cell

(1984)

M.R. Schneider et al.

Structure and function of epigen, the last EGFR ligand

Semin. Cell Dev. Biol.

(2014)

M. Köse

GPCRs and EGFR–cross-talk of membrane receptors in cancer

Bioorg. Med. Chem. Lett.

(2017)

T.-L. Cheng

Functions of rhomboid family protease RHBDL2 and thrombomodulin in wound healing

J. Investig. Dermatol.

(2011)

P. Herrlich et al.

ADAM metalloprotease-released cancer biomarkers

Trends Cancer

(2017)

S. Rose-John

ADAM17, shedding, TACE as therapeutic targets

Pharmacol. Res.

(2013)

H. Nakayama et al.

Cullin 3 regulates ADAMs-mediated ectodomain shedding of amphiregulin

Biochem. Biophys. Res. Commun.

(2018)

H. Kataoka

EGFR ligands and their signaling scissors, ADAMs, as new molecular targets for anticancer treatments

J. Dermatol. Sci.

(2009)

F. Walker

CR1/CR2 Interactions modulate the functions of the cell surface epidermal growth factor receptor

J. Biol. Chem.

(2004)

G.N. Gill

Monoclonal anti-epidermal growth factor receptor antibodies which are inhibitors of epidermal growth factor binding and antagonists of epidermal growth factor-stimulated tyrosine protein kinase activity

J. Biol. Chem.

(1984)

S. Li

Structural basis for inhibition of the epidermal growth factor receptor by cetuximab

Cancer Cell

(2005)

D.W. Threadgill

Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype

Science

(1995)

C.P. Blobel

ADAMs: key components in EGFR signalling and development

Nat. Rev. Mol. Cell Biol.

(2005)

M.F. Lomas et al.

Determination of EGFR signaling output by opposing gradients of BMP and JAK/STAT activity

Curr. Biol.

(2016)

R.S. Herbst et al.

Monoclonal antibodies to target epidermal growth factor receptor-positive tumors: a new paradigm for cancer therapy

Cancer

(2002)

D.S. Salomon et al.

Epidermal growth factor-related peptides and their receptors in human malignancies

Clin. Rev. Oncol./Haematol.

(1994)

C. Messa et al.

EGF, TGF-alpha and EGFR in human colorectal adenocarcinoma

Acta Oncol.

(1998)

V. Rusch

Overexpression of epidermal growth factor receptor and its ligand transforming growth factor alpha is frequent in resectable non-small cell lung cancer but does not predict tumor progression

Clin. Cancer Res.

(1997)

G. Fontanini

Evaluation of epidermal growth factor-related growth factors and receptors and of neoangiogenesis in completely resected stage I-IIIA non-small cell lung cancer- amphiregulin and microvessel count are independent prognostic indicators of survival

Clin. Cancer Res.

(1998)

P. Rieske

A comparative study of epidermal growth factor receptor (EGFR) and MDM2 gene amplification and protein immunoreactivity in human glioblastomas

Pol. J. Pathol.

(1998)

A.J. Ekstrand

Genes for epidermal growth factor receptor, transforming growth factor, and epidermal growth factor and their expression in human gliomas in vivo

Cancer Res.

(1991)

K. Oda et al.

A comprehensive pathway map of epidermal growth factor receptor signaling

Mol. Syst. Biol.

(2005)

E. Tzahar et al.

The ErbB-2/HER2 oncogenic receptor of adenocarcinomas: from orphan-hood to multiple stromal ligands

Biochim. Biophys. Acta

(1998)

Y. Yarden et al.

Untangling the ErbB SignallingNetwork

Nat. Rev.: Mol. Cell Biol.

(2001)

S. Huang

Dual targeting of EGFR and HER3 with MEHD7945A overcomes acquired resistance to EGFR inhibitors and radiation

Cancer Res.

(2013)

B.K. Allen

Large-scale computational screening identifies first in class multitarget inhibitor of EGFR kinase and BRD4

Sci. Rep.

(2015)

S. Guardiola

Peptides targeting EGF block the EGF–EGFR interaction

ChemBioChem

(2016)

N. Kozer

Exploring higher-order EGFR oligomerisation and phosphorylation - a combined experimental and theoretical approach

Mol. Biosyst.

(2013)

D. Stabley et al.

Manipulating the lateral diffusion of surface-anchored EGF demonstrates that receptor clustering modulates phosphorylation levels

Integr. Biol.

(2013)

R. Pinkas-Kramarski

Diversification of Neu differentiation factor and epidermal growth factor signaling by combinatorial receptor interactions

EMBO J.

(1996)

D.M. Danilenko

Neu differentiation factor upregulates epidermal migration and integrin epxression in excisional wounds

J. Clin. Investig.

(1995)

C. Birchmeier et al.

Molecular aspects of mesenchymal- epithelial interactions

Annu. Rev. Cell Biol.

(1993)

D.J. Riese et al.

The cellular response to neuregulins in governed by complex interactions of the erbB receptor family

Mol. Cell. Biol.

(1995)

S. Cohen et al.

Human epidermal growth factor: isolation and chemical and biological properties

Proc. Natl. Acad. Sci. USA

(1975)

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View full text

Epidermal growth factor receptor: Structure-function informing the design of anticancer therapeutics

Highlights

Abstract

Introduction

Section snippets

EGFR-family

New approaches to ectodomain targeting – disrupting oligomerisation

Targeting the transmembrane and juxtamembrane domains of EGFR

The tyrosine kinase domain: structure, mutations, and targeting

EGFR membrane dynamics

EGFR hetero-oligomerisation and clustering

EGFR signaling

EGFR endocytosis and recycling

EGFR crosstalk

Overcoming resistance and new therapeutic strategies based on targeting the EGFR

Conclusions and future directions

Acknowledgements

Declarations of interest

J. Biol. Chem.

Eur. J. Cancer

Int. J. Pharm.

Biochim. Biophys. Acta (BBA)-Biomembr.

Cell

J. Mol. Graph.

Cell

Mol. Cell

Cell

Cell

Cell

Free Radic. Biol. Med.

Semin. Cell Dev. Biol.

Exp. Mol. Pathol.

Neuron

J. Biol. Chem.

Cell

Semin. Cell Dev. Biol.

Bioorg. Med. Chem. Lett.

J. Investig. Dermatol.

Trends Cancer

Pharmacol. Res.

Biochem. Biophys. Res. Commun.

J. Dermatol. Sci.

J. Biol. Chem.

J. Biol. Chem.

Cancer Cell

Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype

Science

ADAMs: key components in EGFR signalling and development

Nat. Rev. Mol. Cell Biol.

Determination of EGFR signaling output by opposing gradients of BMP and JAK/STAT activity

Curr. Biol.

Monoclonal antibodies to target epidermal growth factor receptor-positive tumors: a new paradigm for cancer therapy

Cancer

Epidermal growth factor-related peptides and their receptors in human malignancies

Clin. Rev. Oncol./Haematol.

EGF, TGF-alpha and EGFR in human colorectal adenocarcinoma

Acta Oncol.

Overexpression of epidermal growth factor receptor and its ligand transforming growth factor alpha is frequent in resectable non-small cell lung cancer but does not predict tumor progression

Clin. Cancer Res.

Evaluation of epidermal growth factor-related growth factors and receptors and of neoangiogenesis in completely resected stage I-IIIA non-small cell lung cancer- amphiregulin and microvessel count are independent prognostic indicators of survival

Clin. Cancer Res.

A comparative study of epidermal growth factor receptor (EGFR) and MDM2 gene amplification and protein immunoreactivity in human glioblastomas

Pol. J. Pathol.

Genes for epidermal growth factor receptor, transforming growth factor, and epidermal growth factor and their expression in human gliomas in vivo

Cancer Res.

A comprehensive pathway map of epidermal growth factor receptor signaling

Mol. Syst. Biol.

The ErbB-2/HER2 oncogenic receptor of adenocarcinomas: from orphan-hood to multiple stromal ligands

Biochim. Biophys. Acta

Untangling the ErbB SignallingNetwork

Nat. Rev.: Mol. Cell Biol.

Dual targeting of EGFR and HER3 with MEHD7945A overcomes acquired resistance to EGFR inhibitors and radiation

Cancer Res.

Large-scale computational screening identifies first in class multitarget inhibitor of EGFR kinase and BRD4

Sci. Rep.

Peptides targeting EGF block the EGF–EGFR interaction

ChemBioChem

Exploring higher-order EGFR oligomerisation and phosphorylation - a combined experimental and theoretical approach

Mol. Biosyst.

Manipulating the lateral diffusion of surface-anchored EGF demonstrates that receptor clustering modulates phosphorylation levels