Molecular and Clinical Features of EGFR-TKI-Associated Lung Injury.

The tyrosine kinase activity of epidermal growth factor receptors (EGFRs) plays critical roles in cell proliferation, regeneration, tumorigenesis, and anticancer resistance. Non-small-cell lung cancer patients who responded to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) and obtained survival benefits had somatic EGFR mutations. EGFR-TKI-related adverse events (AEs) are usually tolerable and manageable, although serious AEs, including lung injury (specifically, interstitial lung disease (ILD), causing 58% of EGFR-TKI treatment-related deaths), occur infrequently. The etiopathogenesis of EGFR-TKI-induced ILD remains unknown. Risk factors, such as tobacco exposure, pre-existing lung fibrosis, chronic obstructive pulmonary disease, and poor performance status, indicate that lung inflammatory circumstances may worsen with EGFR-TKI treatment because of impaired epithelial healing of lung injuries. There is limited evidence from preclinical and clinical studies of the mechanisms underlying EGFR-TKI-induced ILD in the available literature. Herein, we evaluated the relationship between EGFR-TKIs and AEs, especially ILD. Recent reports on mechanisms inducing lung injury or resistance in cytokine-rich circumstances were reviewed. We discussed the relevance of cytotoxic agents or immunotherapeutic agents in combination with EGFR-TKIs as a potential mechanism of EGFR-TKI-related lung injury and reviewed recent developments in diagnostics and therapeutics that facilitate recovery from lung injury or overcoming resistance to anti-EGFR treatment.

Blockade of EGFR Activation Promotes TNF-Induced Lung Epithelial Cell Apoptosis and Pulmonary Injury.

Pneumonitis is the leading cause of death associated with the use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) against non-small cell lung cancer (NSCLC). However, the risk factors and the mechanism underlying this toxicity have not been elucidated. Tumor necrosis factor (TNF) has been reported to transactivate EGFR in pulmonary epithelial cells. Hence, we aimed to test the hypothesis that EGFR tyrosine kinase activity regulates TNF-mediated bronchial epithelial cell survival, and that inhibition of EGFR activity increases TNF-induced lung epithelial cell apoptosis. We used surfactant protein C (SPC)-TNF transgenic (tg) mice which overexpress TNF in the lungs. In this model, gefitinib, an EGFR-TKI, enhanced lung epithelial cell apoptosis and lymphocytic inflammation, indicating that EGFR tyrosine kinase prevents TNF-induced lung injury. Furthermore, IL-17A was significantly upregulated by gefitinib in SPC-TNF tg mice and p38MAPK activation was observed, indicative of a pathway involved in lung epithelial cell apoptosis. Moreover, in lung epithelial cells, BEAS-2B, TNF stimulated EGFR transactivation via the TNF-α-converting enzyme in a manner that requires heparin binding (HB)-EGF and transforming growth factor (TGF)-α. These novel findings have significant implications in understanding the role of EGFR in maintaining human bronchial epithelial cell homeostasis and in NSCLC treatment.