Modulation of Pathological Pain by Epidermal Growth Factor Receptor

Abstract

Chronic pain has been widely recognized as a major public health problem that impacts multiple aspects of patient quality of life. Unfortunately, chronic pain is often resistant to conventional analgesics, which are further limited by their various side effects. New therapeutic strategies and targets are needed to better serve the millions of people suffering from this devastating disease. To this end, recent clinical and preclinical studies have implicated the epidermal growth factor receptor signaling pathway in chronic pain states. EGFR is one of four members of the ErbB family of receptor tyrosine kinases that have key roles in development and the progression of many cancers. EGFR functions by activating many intracellular signaling pathways following binding of various ligands to the receptor. Several of these signaling pathways, such as phosphatidylinositol 3-kinase, are known mediators of pain. EGFR inhibitors are known for their use as cancer therapeutics but given recent evidence in pilot clinical and preclinical investigations, may have clinical use for treating chronic pain. Here, we review the clinical and preclinical evidence implicating EGFR in pathological pain states and provide an overview of EGFR signaling highlighting how EGFR and its ligands drive pain hypersensitivity and interact with important pain pathways such as the opioid system.

Keywords: animal models; epidermai growth factor receptor; inflammation; membrane traffic; neuropathic pain; receptor tyrosine kinase.

FIGURE 1

Examples of current and emerging potential therapeutics for treatment of neuropathic pain. (A) Current therapeutics include gabapentinoids that act on the α2δ-1 calcium channel subunit, topical agents with targets such as TRPV1 or voltage-gated sodium channels, opioids, atypical opioids (mixed/partial agonists, some of which have actions as an SNRI or NI), TCAs that act on various distinct targets such as serotonergic, adrenergic and cholinergic systems and fast voltage-gated sodium channels, and SNRIs. (B) Examples of emerging potential targets and therapeutics for neuropathic pain. 5-HT: 5-hydroxytryptamine, CB1/2: cannabinoid receptor type 1/2, Ca_V: voltage-gated calcium channel, EGF: epidermal growth factor, EGFR: epidermal growth factor receptor, EREG: epiregulin, IL: interleukin, IL-6R: interleukin-6 receptor, IL-1R: interleukin-1 receptor, mAChR: muscarinic acetylcholine receptor, MOR: mu-opioid receptor, Na_V voltage-gated sodium channel, NGF: nerve growth factor, NI: norepinephrine reuptake inhibitor, SNRI: selective serotonin reuptake inhibitor, TCA: tricyclic antidepressant, TNF: tumor necrosis factor, TNFR: tumor necrosis factor receptor, TrkA: tropomyosin receptor kinase A, TRPV1: transient receptor potential cation channel subfamily V member 1.

FIGURE 2

EGFR structure, ligand-binding, and signaling pathways. In the basal state, EGFR exists in an autoinhibited conformation. Ligand-binding allows for the formation of homo- or heterodimers, which activates EGFR intrinsic tyrosine kinase domains and ensues signal transduction, shown here as an EGFR homodimer with one ligand bound. Various signalling pathways are initiated by the active EGFR, such as Ras-Erk, JAK/SFK-STAT, and PI3K-Akt. Regarding EGFR-PI3K-Akt signalling, EGFR autophosphorylation at Y1068 allows for the activation of class IA PI3K. The active PI3K subsequently phosphorylates PI(4,5)P₂ (PIP₂) into PI(3,4,5)P₃, which recruits kinases PDK1 and Akt to the plasma membrane. There, Akt is phosphorylated by PDK1 and mTORC2 at T308 and S473, respectively. EGFR: epidermal growth factor receptor, JAK: Janus kinase, SFK: Src-family kinase, STAT: signal transducer and activator of transcription, PI3K: phosphoinositide 3-kinase, PDK1: phosphoinositide-dependent kinase 1, mTORC: mechanistic target of rapamycin complex, TSC: tuberous sclerosis complex, SOS: son of sevenless, Grb2: growth factor receptor-bound protein 2, Gab1: Grb2-associated binding protein 1.

FIGURE 3

EGF/EREG-EGFR and NGF-TrkA signaling mechanisms that contribute to pain/sensitization. (A) EREG-mediated sensitivity to formalin and capsaicin involves TRPV1. (B) Similarly, NGF mediates sensitivity to capsaicin and formalin. NGF-TrkA signalling mediates traffic of TRPV1 to the plasma membrane through a PI3K-dependent mechanism. The mechanisms by which NGF mediates sensitivity through these signaling intermediates is more well-characterized and thus, the mechanisms by which EREG-EGFR signaling promotes sensitivity warrants further investigation. The mechanisms by which other EGFR ligands mediate sensitivity are incompletely understood. Additionally, whether and how EREG-EGFR and EGF-EGFR signaling may promote sensitivity to distinct stimuli in various animal models remain to be elucidated.

FIGURE 4

EGFR may modulate immune responses and opioid tolerance by controlling receptor localization and receptor crosstalk. (A) EGFR is required for aspects of TLR4 signalling as well as TLR4 recycling and cell-surface enrichment following LPS stimulation. (B) EGFR and opioid receptor crosstalk leading to opioid receptor internalization and downregulation that may contribute to tolerance.