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Oncotarget, 2021, Vol. 12, (No. 13), pp: 1321-1322
Editorial

Mechanisms of gefitinib-induced interstitial pneumonitis: whyand how the TKI perturbs innate immune systems?
Tomohiro Kagi, Takuya Noguchi and Atsushi Matsuzawa
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 ofsolid tumors, including inoperable non-small cell lungcancer with EGFR mutation [1]. Although gefitinib isa molecular target drug, several studies have revealed
that gefitinib targets unexpected proteins besides EGFR,
which may be associated with the serious side effects ofgefitinib, such as interstitial pneumonitis [1–3]. Interstitial
pneumonia refers to potent inflammation of lung tissuecaused by over-activation of the immune system triggeredby drugs or viral infections, resulting in dyspnea andrespiratory 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 ofgefitinib-induced inflammation is an effective approachto overcome interstitial pneumonia initiated by gefitinib.
We have recently demonstrated that gefitinib
markedly increases the production of IL-1β inmacrophages 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 NLRP3inflammasome plays a critical role in the initiation ofinterstitial pneumonitis [5]. To date, several causal factorsof 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 productionof mitochondrial ROS, which is responsible for theactivation on the NLRP3 inflammasome. However, theFigure 1: Gefitinib initiates sterile inflammation via two distinct mechanisms. (I) Gefitinib promotes IL-1β release bystimulating the NLRP3 inflammasome. (II) Gefitinib promotes poly-ADP-ribosylation and release of HMGB1 via PARP-1 activation.
Released-HMGB1 binds RAGE (receptor for advanced glycation endproducts) or TLR (Toll-like receptor) 2/4, which additively promotes
IL-1β release [5].
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OncotargetACKNOWLEDGMENTS

mechanisms by which gefitinib initiates mitochondrial
damage have remained challenging. In this regard, there
are two possible mechanisms by which gefitinib produces
mitochondrial ROS. One is that gefitinib structurally
damages mitochondria, and then accumulation ofdamaged mitochondria triggers the activation of theNLRP3 inflammasome [7]. To investigate this possibility,
other TKIs that have different structures from gefitinib
should be comprehensively tested whether they canactivate the NLRP3 inflammasome. The other is that
nonspecific inhibition of tyrosine kinases by gefitinib
disrupts mitochondrial homeostasis. Indeed, it is known
that several tyrosine kinases participate in maintenance ofmitochondrial homeostasis by regulating the mitochondrial
electron transfer system [8, 9]. Therefore, the off-target
effects of gefitinib on mitochondrial tyrosine kinases may
disrupt mitochondrial homeostasis. In this case, to identify
the mitochondrial tyrosine kinases that are sensitive togefitinib may lead to understanding causal mechanisms ofgefitinib-induced inflammation.
We have also demonstrated that gefitinib promotes
high-mobility group box 1 (HMGB1) release [5]. The
release of HMGB1 promotes a positive feedback loop ofthe NLRP3 inflammasome activation, leading to excessive
inflammation. HMGB1 therefore has emerged as a key
mediator of inflammation. Mechanistically, it is interestingthat gefitinib can actively release HMGB1 without theNLRP3 inflammasome. Gefitinib-induced mitochondrial
ROS elicit DNA damage, which activates poly (ADPribose) polymerase-1 (PARP-1). Then, activated PARP1 seems to promote the HMGB1 release via poly-ADPribosylation of HMGB1 [5].
Together our study has uncovered that gefitinib
initiates sterile inflammation via two distinct mechanisms,
and has also identified IL-1β and HMGB1 as critical
determinants of gefitinib-induced inflammation (Figure 1)[5]. Interestingly, a recent study has identified papaverine
as an inhibitor of HMGB1, and has demonstrated thatpapaverine can inhibit HMGB1-mediated inflammation[10]. Papaverine is commonly prescribed as anantispasmodic drug, which makes it possible to give an
opportunity for drug repositioning. In addition, a seriesof NLRP3 inhibitors and IL-1β neutralizing antibodies
are also potentially available as therapeutic agents for
gefitinib-induced interstitial pneumonia. In any case,
it is imperative to develop methods to prevent druginduced interstitial pneumonia. To analyze the effects ofpharmaceuticals on innate immune systems is expected
to be a reliable approach to overcome drug-induced
interstitial pneumonia.

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We thank all members of Lab of Health Chemistry
for helpful discussions.

CONFLICTS OF INTEREST
Authors have no conflicts of interest to declare.
Atsushi Matsuzawa: Laboratory of Health Chemistry,Graduate School of Pharmaceutical Sciences, Tohoku
University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, Miyagi
980-8578, Japan
Correspondence to: Atsushi Matsuzawa,email atsushi.matsuzawa.c6@tohoku.ac.jp
Keywords: gefitinib; interstitial pneumonitis; tyrosine kinase
inhibitor; inflammation; NLRP3 inflammasome
Received: April 26, 2021
Published: June 22, 2021

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Copyright: © 2021 Kagi et al. This is an open access article
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