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A clinical drug library screen identifies clobetasol propionate as an NRF2 inhibitor with potential therapeutic efficacy in KEAP1 mutant lung cancer

Oncogene volume 36, pages 5285–5295 (2017)Cite this article

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Abstract

The Kelch-like ECH-associated protein 1 (KEAP1)–nuclear factor E2-related factor 2 (NRF2)pathway has a central role in cellular antioxidant defense. NRF2 activation due to KEAP1 or NRF2 mutations occurs frequently in many cancers, suggesting that NRF2 inhibition could be a promising therapeutic strategy. However, no potent NRF2 inhibitors are clinically available to date. To develop potent NRF2 inhibitors for therapeutic purpose, we screened ~4000 clinical compounds and determined clobetasol propionate (CP) as the most potent NRF2 inhibitor. Mechanistically, CP prevented nuclear accumulation and promoted β-TrCP-dependent degradation of NRF2 in a glucocorticoid receptor- and a glycogen synthase kinase 3 (GSK3)-dependent manner. As a result, CP induced oxidative stress and strongly suppressed the anchorage-independent growth of tumors with KEAP1 mutation, but not with the wild-type KEAP1. Further, CP alone or in combination with rapamycin strongly inhibited the in vitro and in vivo growth of tumors harboring mutations in KEAP1 or both KEAP1 and LKB1 that are frequently observed in lung cancer. Thus, CP could be a repurposed therapeutic agent for cancers with high NRF2 activity. We also proposed that the use CP and rapamycin in combination could be a potential therapeutic strategy for tumors harboring both KEAP1 and LKB1 mutations.

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Acknowledgements

We thank Y-GL and S-HP for the technical assistance provided. The clinical compound library (with 1887 compounds) was provided by the Korea Chemical Bank (KCB) from the Korea Research Institute of Chemical Technology (KRICT). This work was supported by grants from the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (S2014-A0251-00001) and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (S2014-A0403-00067) to S-MJ and the National Cancer Center of Korea (NCC1410670) to S-YK.

Author contributions

S-MJ designed the experiments. E-JC, B-JJ, H-SY and E-AS performed the in vitro experiments. S-YK and S-HL designed and performed the xenograft experiment. H-JK, SJ and S-MJ analyzed the data and S-MJ wrote the manuscript.

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  1. E-J Choi, B-J Jung and S-H Lee: These authors contributed equally to this work.

Authors and Affiliations

  1. College of Pharmacy, Ajou University, Suwon, Republic of Korea

    E-J Choi, B-J Jung, H-S Yoo, E-A Shin & S-M Jeon

  2. Cancer Cell and Molecular Biology Branch, Research Institute, National Cancer Center, Goyang, Republic of Korea

    S-H Lee & S-Y Kim

  3. College of Pharmacy, Kangwon National University, Chuncheon, Republic of Korea

    H-J Ko

  4. Convergence Research Center for Functional Plant Products, Advanced Institutes of Convergence Technology, Yeongtong-gu, Suwon, Republic of Korea

    H-J Ko

  5. Department of Biomedical Sciences, University of Ulsan School of Medicine, Asan Medical Center, Seoul, Republic of Korea

    S Chang

  6. Institute of Pharmaceutical Science and Technology, Ajou University, Suwon, Republic of Korea

    S-M Jeon

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  1. E-J Choi
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Choi, EJ., Jung, BJ., Lee, SH. et al. A clinical drug library screen identifies clobetasol propionate as an NRF2 inhibitor with potential therapeutic efficacy in KEAP1 mutant lung cancer. Oncogene 36, 5285–5295 (2017). https://doi.org/10.1038/onc.2017.153

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