Bucillamine Prevents Afatinib-Mediated Inhibition of Epidermal Growth Factor Receptor Signaling
1
Division of Integrated Information for Pharmaceutical Sciences, Department of Clinical Pharmacy, Iwate Medical University School of Pharmacy, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate 028-3694, Japan
2
Department of Pharmacy, Iwate Medical University Hospital, 2-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate 028-3695, Japan
*
Author to whom correspondence should be addressed.
Pharmaceuticals 2019, 12(4), 165; https://doi.org/10.3390/ph12040165
Received: 30 September 2019 / Revised: 29 October 2019 / Accepted: 5 November 2019 / Published: 7 November 2019
(This article belongs to the Special Issue Zebrafish as a Powerful Tool for Drug Discovery)
Molecular targeting therapies often cause characteristic adverse effects, such as skin rash during anti-epidermal growth factor receptor (EGFR) therapies, making treatment continuation difficult. In contrast, skin symptoms induced by EGFR inhibition are strongly correlated with the overall survival of the therapies. Therefore, controlling adverse effects not only facilitates treatment continuation but also increases clinical benefits. In this study, we proposed a novel strategy for reducing EGFR–tyrosine kinase inhibitor (TKI)-induced adverse effects in nontumorous organs by repositioning approved medicines using a zebrafish model. We developed a model system for evaluating chemical quenchers of afatinib, a clinically available irreversible EGFR-TKI, by scoring the inhibition of afatinib-induced hyperformation of lateral line neuromasts in zebrafish larvae. Bucillamine, an antirheumatic drug, was identified as an afatinib quencher in the zebrafish system and inhibited TKI activity in vitro. In addition, bucillamine restored EGFR autophosphorylation and downstream signaling in afatinib-treated A431 cells. Thus, topical bucillamine is a potential reliever of irreversible EGFR-TKI-induced skin rash. The zebrafish model can be applied to a screening for quenchers of other anti-EGFR-targeting therapies, including reversible TKIs and biologics.
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Keywords:
adverse effect; EGFR-TKI; skin rash
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MDPI and ACS Style
Nishiya, N.; Murai, M.; Hosoda, A.; Yonezawa, H.; Omori, N. Bucillamine Prevents Afatinib-Mediated Inhibition of Epidermal Growth Factor Receptor Signaling. Pharmaceuticals 2019, 12, 165. https://doi.org/10.3390/ph12040165
AMA Style
Nishiya N, Murai M, Hosoda A, Yonezawa H, Omori N. Bucillamine Prevents Afatinib-Mediated Inhibition of Epidermal Growth Factor Receptor Signaling. Pharmaceuticals. 2019; 12(4):165. https://doi.org/10.3390/ph12040165
Chicago/Turabian StyleNishiya, Naoyuki; Murai, Moeka; Hosoda, Ayumi; Yonezawa, Honami; Omori, Norikazu. 2019. "Bucillamine Prevents Afatinib-Mediated Inhibition of Epidermal Growth Factor Receptor Signaling" Pharmaceuticals 12, no. 4: 165. https://doi.org/10.3390/ph12040165
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