Targeting EGFR signalling in chronic lung disease: therapeutic challenges and opportunities

Abstract

Chronic respiratory diseases, including pulmonary fibrosis, chronic obstructive pulmonary disease (COPD) and lung cancer, are the second leading cause of death among Europeans. Despite this, there have been only a few therapeutic advances in these conditions over the past 20 years. In this review we provide evidence that targeting the epidermal growth factor receptor (EGFR) signalling pathway may represent a novel therapeutic panacea for treating chronic lung disease. Using evidence from human patient samples, transgenic animal models, and cell and molecular biology studies we highlight the roles of this signalling pathway in lung development, homeostasis, repair, and disease ontogeny. We identify mechanisms underlying lung EGFR pathway regulation and suggest how targeting these mechanisms using new and existing therapies has the potential to improve future lung cancer, COPD and pulmonary fibrosis patient outcomes. @ERSpublications Deregulated EGFR pathway signalling is a common event and an important therapeutic target for many chronic lung diseases

DUOX1 mediates persistent epithelial EGFR activation, mucous cell metaplasia, and airway remodeling during allergic asthma

“…Collectively, these findings indicate that epithelial DUOX1 mediates a number of critical features of allergic airway inflammation, most notably neutrophilia, mucous metaplasia, subepithelial fibrosis, and airways hyperresponsiveness. Since each of these outcomes have in previous studies been linked with enhanced epithelial activation of EGFR (12,15,16), our findings are consistent with the hypothesis that DUOX1 contributes to these phenotypes largely by promoting persistent EGFR activation within the airway epithelium.…”

“…Airway epithelial EGFR activation has been linked with neutrophilic inflammation in severe human asthma (11) and with HDM-induced neutrophilia in mice (15), suggesting that the observed contribution of DUOX1 to neutrophilic inflammation in the present studies is related to its role in epithelial EGFR activation. Another critical feature of allergic airway inflammation that has been strongly associated with airway epithelial EGFR activation is the development of mucous goblet cell metaplasia (12,13). As expected, HDM-induced allergic inflammation was associated with increased presence of airway mucus, as visualized by PAS staining ( Figure 3B), and enhanced lung tissue expression of the mucous metaplasia genes Muc5ac, Clca1, and Postn (Supplemental Figure 1B), and each of these out- Representative histochemical images are shown, and dot plots represent mean ± SD of 8-12 replicates from 3 independent experiments.…”

“…38, 39), the contribution of DUOX1 to allergic inflammation was found to be closely related to its role in persistent oxidant-dependent epithelial activation of EGFR and consequent production of neutrophil chemokines and type 2 cytokines such as IL-13, which results in promotion of neutrophilic inflammation, mucous metaplasia, subepithelial fibrotic remodeling, and central airway resistance. The importance of airway EGFR activation to these various features of allergic asthma is well recognized (11,15,17), but existing EGFR tyrosine kinase inhibitors have not been evaluated for clinical application in chronic lung diseases such as asthma, because of the broad role of EGFR in various organ systems and reported adverse effects that are tolerable in severe or fatal lung diseases, such as lung cancer, but not in lung diseases that are not immediately life-threatening (12,(18)(19)(20). The fact that DUOX1 expression is largely restricted to epithelial lineages (39), including the lung, renders it a more appealing therapeutic target, with the potential of avoiding unwanted side effects associated with EGFR inhibitors administered systemically.…”

“…Epithelial EGFR activation contributes to several important features of asthma, including the activation of a chronic wound response within the airways characterized by airway remodeling, mucous metaplasia, and neutrophilic inflammation (11)(12)(13). Moreover, our recent findings indicate that epithelial EGFR activation also mediates allergen-induced epithelial secretion of the alarmin IL-33 and subsequent activation of type 2 inflammatory responses (14).…”

The ambition of theEuropean Respiratory Journal: chapter 3

“…The first three Back to Basics reviews covered subjects as diverse as EGFR signalling [6], medical nanoparticles [7] and the latest advances in our knowledge of CFTR dysfunction [8]. This is an exciting new feature, and we look forward to watching it develop.…”