• Ning-Ning Liu, Jia Zhou, Tong Jiang, Maureen Tarsio, Feifei Yu, Xuehan Zheng, Wanjun Qi, Lin Liu, Jing-Cong Tan, Luqi Wei, Jun Ding, Jingquan Li, Lingbing Zeng, Biao Ren, Xiaotian Huang, Yibing Peng, Yong-Bing Cao, Yanbin Zhao, Xin-Yu Zhang, Patricia M Kane, Changbin Chen, and Hui Wang.
• State Key Laboratory of Oncogenes and Related Genes, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: liuningning@shsmu.edu.cn.
• Transl Res. 2022 Sep 1; 247: 39-57.

AbstractFungal infection threatens human health worldwide due to the limited arsenal of antifungals and the rapid emergence of resistance. Epidermal growth factor receptor (EGFR) is demonstrated to mediate epithelial cell endocytosis of the leading human fungal pathogen, Candida albicans. However, whether EGFR inhibitors act on fungal cells remains unknown. Here, we discovered that the specific EGFR inhibitor osimertinib mesylate (OSI) potentiates azole efficacy against diverse fungal pathogens and overcomes azole resistance. Mechanistic investigation revealed a conserved activity of OSI by promoting intracellular fluconazole accumulation via inhibiting Pdr5 and disrupting V-ATPase function via targeting Vma1 at serine 274, eventually leading to inactivation of the global regulator TOR. Evaluation of the in vivo efficacy and toxicity of OSI demonstrated its potential clinical application in impeding fluconazole resistance. Thus, the identification of OSI as a dual action antifungal with co-targeting activity proposes a potentially effective therapeutic strategy to treat life-threatening fungal infection and overcome antifungal resistance.Copyright © 2022 Elsevier Inc. All rights reserved.

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