EGFR inhibitors
Studies suggest that inhibiting EGFR signaling might prevent an excessive fibrotic response to SARS-CoV and other respiratory infections (like that characteristic of COVID-19). EGFR plays a role in interstitial lung disease, and interaction between EGF and TFG-beta signaling is believed to drive development of fibrosis (116) (117). The role of EGFR signaling in the development of lung fibrosis is complex, though, with data suggesting both profibrotic and antifibrotic roles for EGFR signaling, at least in part seeming to depend on the trigger for fibrosis (13). Gefitinib inhibited TGF-beta1 induction of fibrosis in vivo (118) and inhibited bleomycin-induced fibrosis in a mouse model (119), and erlotinib was reported to block fibrosis development in a variety of in vivo models (13).
TGF-beta induces the expression of EGFR ligands, which in turn activate EGFR. Of relevance, TGF-beta was one of several pro-inflammatory cytokines that were observed to be highly upregulated in SARS-CoV patients (120) (121) (122), and mouse models of SARS-CoV infection showed interferon, cytokine and lung-associated wound-healing and ARDS-related genes (123). These findings are consistent with TGF-beta being profibrotic, as has been demonstrated in animal models (124). The kinase inhibitor, sorafenib, attenuated bleomycin-induced pulmonary fibrosis in a preclinical model (125) and ameliorated fibrosis in liver fibrosis models through STAT3 inhibition and downregulation of TGF-beta- and PDGFRβ-mediated pathways of fibrogenesis (126).
The EGFR inhibitor, osimertinib, is metabolized and broken down into two pharmacologically active metabolites (AZ7550 and AZ5104), which circulate at around 10% of the concentration of the parent compound (Table 3). One metabolite, AZ5104, which is more potent than osimertinib, downregulates Th17-related cytokine production via inhibition of SRC-ERK-STAT3 (127) (Table 2).