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Contents

Introduction

Tyrosine kinase inhibitors (TKIs)

The pathogenesis of lung fibrosis and epidermal growth factor receptor (EGFR)

Lung metabolic function

Conclusion

Introduction

The lung-specific toxicity induced by epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for the treatment of non-small cell lung cancer (NSCLC) has emerged as a critical side-effect (1–7). Although the clinical features of the pulmonary side-effects of TKIs have been characterized (8–10), the details of the molecular mechanisms in the development of this lung-specific toxicity remain to be elucidated. The aim of this review was to provide further insight into the molecular mechanisms of lung-specific toxicity in the context of treatment with EGFR-TKIs.

Tyrosine kinase inhibitors (TKIs)

Recent advances in molecular targeted therapy have demonstrated improved response rates and progression free survival, particularly with TKIs which may act on the EGFR, in NSCLC patients (11,12). Tyrosine kinases are enzymes that transfer the terminal phosphate from ATP to tyrosine residues in order to activate them, and the signaling pathways through receptor tyrosine kinases (RTKs) have been demonstrated to play a role in cancer development. Therefore, different types of TKIs have been developed and used in the treatment of cancer. EGFR-TKIs were adapted for lung cancer treatment since EGFR is frequently overexpressed and occasionally mutated in NSCLC cells (13–15).

There are two types of TKIs: non-receptor TKIs and receptor TKIs. The former TKIs bind to the active site of a non-receptor tyrosine kinase to prevent phosphorylation. Imatinib is a non-receptor TKI, which is used for the treatment of chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GISTs) and other diseases (16). The latter TKIs are able to bind to the active site of a RTK and some may exhibit a selective inhibitory effect on a certain RTK. Erlotinib and gefitinib are selective inhibitors of the EGFR tyrosine kinase domain. Erlotinib is used for the treatment of pancreatic carcinomas and NSCLC, while gefitinib is used for the treatment of NSCLC (9). A number of TKIs targeting several cancers have been approved for clinical use, and numerous newly developed TKIs are currently undergoing clinical trials (17).

Lung-specific toxicities induced by treatment with TKIs are rare (8). However, lung fibrosis associated with EGFR-TKIs is the most prominent in specific toxicity (9). The incidence of lung fibrosis ranges from 0.2 to 1.1% in erlotinib-treated patients and from 0.38 to 2.0% in gefitinib-treated patients (9). Additionally, a higher incidence of gefitinib-induced lung fibrosis is observed in Japanese patients (1). The predictive risk factors for the development of lung fibrosis include male gender, smoking history and antecedent lung fibrosis (4).

Randomized controlled trials (RCTs) of a new TKIs (originally BIBF 1120) assessing lung fibrosis were recently launched (18). This TKI is a per os active fibroblast growth factor receptor (FGFR), vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptors (PDGFR)-TKI that is supposed to be effective against lung fibrosis since certain tyrosine kinase pathways have been demonstrated to be included in the development of lung fibrotic lesions (18). However, lung fibrosis is one of the adverse effects induced by an active selective EGFR-TKI for the treatment of NSCLC (8–10). These results indicate that only the EGFR pathway in the tyrosine kinase activities may account for the lung fibrosis in the patients treated with these drugs. Additionally, the EGFR-dependent pathway may be essential for the maintenance of the lung parenchyma consisting of the alveolar epithelium.

The pathogenesis of lung fibrosis and epidermal growth factor receptor (EGFR)

A unifying mechanism that is able to completely explain all fibrotic lung diseases remains to be elucidated. The original hypothesis regarding the pathogenesis of lung fibrosis indicated that a chronic inflammatory process may activate the fibrotic response through an anti-inflammatory mechanism disorder and a persisting exposure to an injurious antigen, thus resulting in the migration of hyperproliferative fibroblasts and subsequent production of the extracellular matrix (19). However, current evidence suggests that the sequentially injured and abnormally activated alveolar epithelial cells (AECs) are sufficient to drive the fibrotic response. These injured AECs release certain types of mediators, including transforming growth factor-β, which are able to induce the formation of fibroblast foci through the epithelial to mesenchymal transition (EMT) as well as the proliferation and transformation of residential mesenchymal cells (20).

EGFR, a cell surface receptor, is activated by binding to ligands, including the epidermal growth factor and transforming growth factor α (TGF-α). Activated tyrosine kinase through the EGFR regulates cell growth, apoptosis and differentiation (21). EGFR is a member of the ErbB family, which includes EGFR (ErbB-1), HER2/c-neu (ErbB-2), Her 3 (ErbB-3) and Her 4 (ErbB-4) (22). Previous studies have demonstrated that EGFR and TGF-α played an important role in the development of lung fibrosis (23,24). Alveolar type II cells in fibrotic lung tissues express higher levels of EGFR in comparison to cells in normal lung tissue, thus resulting in focal hyperplasia of alveolar epithelial cells. This indicates that epithelial regeneration through the EGFR-mediated pathways may be a potential mechanism for recovery from lung injury (25,26). Therefore, EGFR inhibition induced by EGFR-TKIs is suggested to impair the ability of the type II cells to proliferate in order to regenerate the epithelial cells and augment lung fibrosis. TGF-α is a ligand that binds to EGFR and functions as a mitogen, which encourages cultured epithelial cells, fibroblasts and endothelial cells to proliferate. TGF-α has protective roles against lung injury, which include the attenuation of inflammation and the reduction of pulmonary edema (24). The blockade of EGFR-dependent phosphorylation by EGFR-TKIs inhibits EGFR-mediated signaling, resulting in the impairment of these protective roles by TGF-α and the exacerbation of lung fibrosis (27).

Lung metabolic function

The lung is extensively affected by exposure to internal agents in the systemic circulation as well as exposure to airborne particulates through the mouth and nose. Pulmonary vasculature receives the entire cardiac output. Similar to the liver, the lung is a metabolic organ containing chemical-metabolizing enzymatic systems, including P450 enzymes. Therefore, circulating agents, including toxicants, may be extracted from the plasma and become concentrated in the lung (28). Exposure to airborne particulates, including viruses, bacteria, vapors, fumes, dusts, gases and mists, are supposed to cause particulates-related lung diseases, e.g., lung fibrosis.

Although the average concentrations of P450 enzymes in the lung have been identified to be lower compared with that in the liver, alveolar type II epithelial cells and Clara cells appear to possess a higher P450 enzyme concentration (29). The high concentration of these enzymes in certain lung cell types appears to accelerate P450-dependent bioactivation, which subsequently generates highly toxic metabolic products. Lung exposure to these toxicants is able to induce epithelial injury, which may be associated to the development of lung-selective toxicity (29,30).

Pyrrolizidine alkaloids (i.e., monocrotaline), included in various plants belonging to the Crotalaria and Sencicio genera, cause pulmonary hypertension in animal models (31). Pyrrolizidine alkaloids have been demonstrated to transit to alkylating agents through P450-dependent bioactivation in the liver, which is transported via the systemic circulation to the lung vasculature and may induce pulmonary arterial hypertension as well as pulmonary vascular remodeling (32). Similar to pyrrolizidine alkaloids, EGFR-TKIs are metabolized by P450 3A4 enzymes, which are predominantly present in the liver (33). Therefore, it is possible that toxic metabolic products from these TKIs, through P450-dependent bioactivation in the liver, may be transported to the lung and induce direct lung epithelial injury. Gefitinib and erlotinib are EGFR-TKIs and have similar chemical backbone structures. However, patients treated with gefitinib have a higher incidence of TKI-induced lung fibrosis compared with those treated with erlotinib (9). Gefitinib has been demonstrated to be more susceptible to P450-mediated metabolism in liver compared with erlotinib (34), which may contribute to the higher concentration of toxic metabolic products from gefitinib than erlotinib in the lung. The different susceptibilities between both TKIs to the liver metabolizing enzymes may therefore explain the different incidence of TKI-induced lung toxicity in the patients treated with gefitinib and erlotinib.

Conclusion

Patients with any coincidental interstitial pneumonia, epithelial regeneration and restoration of the barrier function through EGFR-dependent epithelial cell proliferation may be stimulated by continuous unknown epithelial injury. Patients with predictive risk factors for the development of lung fibrosis (4) may have a reduced ability to regenerate and restore epithelial cells due to a poor functional status from cancer development. A decrease in pulmonary epithelial cell regeneration through the blockade of EGFR-dependent phosphorylation may play an important role in the development of EGFR-TKIs lung-selective toxicity.

The unique environment of the lung, where epithelial cells are exposed to internal agents and airborne particulates, may induce and/or accelerate the lung-specific toxicity induced by EGFR-TKIs.

Acknowledgements

This study was supported by research grants from the Respiratory Failure Research Group and the Cardiovascular Diseases Research Group (9–19,22–33) from the Ministry of Health, Labor and Welfare (Japan), and a Grant-in-Aid for Scientific Research (Category C; Grant No. 22590851) from the Japanese Ministry of Education and Science, and the Takeda Science Foundation.

References