Figure 3–
Clinically approved and in-development epidermal growth factor receptor (EGFR) signalling pathway inhibitors for chronic respiratory disease. Three strategies are used to antagonise aberrant EGFR signalling. First, monoclonal antibodies bind the extracellular domain of epidermal growth factor (EGF) receptors and prevent endogenous ligand engagement, thereby attenuating downstream pathway activation (cetuximab and trastuzumab). Secondly, small molecule tyrosine kinase inhibitors target the intracellular portion of EGF receptors; in the absence of kinase activity EGFR autophosphorylation and downstream signalling is inhibited (erlotinib, gefitinib, lapatinib, HKI-272 and BIBW-2948). Finally, small molecule inhibitors which target specific downstream EGFR signalling pathway components have also been developed and may exhibit clinical efficacy in chronic respiratory disease (ARRY-142886, PX-866, rapamycin, SDZ RAD, everolimus, ruxolitinib, perifosine, selumetinib and sorafenib). PI3K: phosphatidylinositol-3-kinase; PIP3: phosphatidylinositol (3,4,5)-triphosphate; Akt: protein kinase B; GSK3: glycogen synthase kinase 3; mTOR: mammalian target of rapamycin; MEK: MAPK kinase; ERK: extracellular signal-regulated kinase; JAK: Janus kinase; STAT: signal transducer and activator of transcription.