Mechanisms of gefitinib-induced interstitial pneumonitis: why and how the TKI perturbs innate immune systems?

Abstract

Gefitinib is a representative tyrosine kinase inhibitor (TKI) that blocks the tyrosine kinase activity of epidermal growth factor receptor (EGFR), and thereby exerts anticancer activity against various types of solid tumors, including inoperable non-small cell lung cancer with EGFR mutation [1]. Although gefitinib is a molecular target drug, several studies have revealed that gefitinib targets unexpected proteins besides EGFR, which may be associated with the serious side effects of gefitinib, such as interstitial pneumonitis [1–3]. Interstitial pneumonia refers to potent inflammation of lung tissue caused by over-activation of the immune system triggered by drugs or viral infections, resulting in dyspnea and respiratory failure. In particular, infiltration of immune cells into the interstitium and concomitant increase in the amount of pro-inflammatory cytokines are known to play an important role in pathogenesis of interstitial pneumonia [4]. Therefore, to elucidate mechanisms of gefitinib-induced inflammation is an effective approach to overcome interstitial pneumonia initiated by gefitinib. We have recently demonstrated that gefitinib markedly increases the production of IL-1β in macrophages by stimulating the NLRP3 inflammasome, and MCC950, the specific inhibitor of the NLRP3 (NACHT, LRR and PYD-containing protein 3) inflammasome, clearly suppresses the lung inflammation triggered by gefitinib in vivo, suggesting that the NLRP3 inflammasome plays a critical role in the initiation of interstitial pneumonitis [5]. To date, several causal factors of the NLRP3 inflammasome activation have been proposed, such as potassium efflux, calcium overload, and mitochondrial reactive oxidative species (ROS) [6]. Interestingly, our study has shown that gefitinib causes mitochondrial damage followed by production of mitochondrial ROS, which is responsible for the activation on the NLRP3 inflammasome. However, the Editorial