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

Oncogene
E-J ChoiS-M Jeon

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 co...Continue Reading

References

Jul 21, 2004·Cancer Cell·Reuben J ShawLewis C Cantley
Mar 21, 2006·Journal of the American Academy of Dermatology·Sharon E Jacob, Tace Steele
Jul 11, 2006·Lung Cancer : Journal of the International Association for the Study of Lung Cancer·Diansheng ZhongWei Zhou
Oct 6, 2006·PLoS Medicine·Anju SinghShyam Biswal
Apr 5, 2007·Nature Protocols·Vanicha Vichai, Kanyawim Kirtikara
Dec 1, 2007·Proceedings of the National Academy of Sciences of the United States of America·Xiu Jun WangC Roland Wolf
Oct 11, 2008·Free Radical Biology & Medicine·Kah Poh TanShinya Ito
Apr 18, 2009·Science·Sebastiaan H MeijsingKeith R Yamamoto
Feb 1, 2006·Expert Opinion on Therapeutic Patents·Giorgio V Scagliotti, Giovanni Selvaggi
Apr 8, 2010·Molecular Endocrinology·Rachel SpokoiniRonit Vogt Sionov
May 15, 2010·International Journal of Dermatology·Siamak Moghadam-Kia, Victoria P Werth
Oct 20, 2010·Proceedings of the National Academy of Sciences of the United States of America·Yijun GaoHongbin Ji
Jan 6, 2011·Proceedings of the National Academy of Sciences of the United States of America·Dongmei RenDonna D Zhang
Apr 13, 2011·The Journal of Cell Biology·Yoshihiro InamiMasaaki Komatsu
Apr 26, 2011·Methods in Molecular Biology·Johan van MeerlooJacqueline Cloos
Jul 20, 2012·Nature Reviews. Cancer·Michael B Sporn, Karen T Liby
Sep 11, 2012·Nature·UNKNOWN Cancer Genome Atlas Research Network
Jun 12, 2013·Investigational New Drugs·M SlingerlandH Gelderblom
Jun 19, 2013·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Yao-Chun ZhangEng-Hui Chew
Aug 21, 2013·Trends in Pharmacological Sciences·Mahita Kadmiel, John A Cidlowski
Oct 22, 2013·Genes & Development·Melba C Jaramillo, Donna D Zhang
Nov 30, 2013·Nature Reviews. Drug Discovery·Chiara GorriniTak W Mak
Dec 11, 2013·Cancer Research·Bridgid E HastMichael B Major
Feb 20, 2014·Proceedings of the National Academy of Sciences of the United States of America·Brandon FaubertRussell G Jones
May 16, 2014·Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer·Jacob M KaufmanDavid P Carbone
Jun 5, 2014·BioMed Research International·José Manuel Calderón-MontañoMiguel López-Lázaro
Aug 1, 2014·Nature·UNKNOWN Cancer Genome Atlas Research Network
Oct 24, 2014·Cancer Research·Shasha TaoDonna D Zhang
May 11, 2015·Pharmacology & Therapeutics·Nora SundahlIlse M Beck
Jun 29, 2015·Free Radical Biology & Medicine·Yue GuoAh-Ng Tony Kong
Jun 29, 2015·Free Radical Biology & Medicine·Takafumi Suzuki, Masayuki Yamamoto

❮ Previous
Next ❯

Citations

Sep 20, 2018·International Journal of Cancer. Journal International Du Cancer·Yoojin NohSooyoung Shin
Feb 28, 2019·Journal of Cellular and Molecular Medicine·Hong-Sheng ZhangYing-Hui Huang
Jan 19, 2019·Archives of Pharmacal Research·Soo-Youl Kim
Dec 19, 2018·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Derek LeeCarmen Chak-Lui Wong
Apr 1, 2019·Cancer Medicine·Shijia WuYongheng Bai
Jan 18, 2020·Future Medicinal Chemistry·Hongzhi LinHaopeng Sun
Mar 5, 2020·Archives of Pharmacal Research·Eun-Ji Choi, Sang-Min Jeon
Sep 13, 2019·Cell Communication and Signaling : CCS·Jiang-Jiang QinWei-Dong Zhang
Aug 10, 2019·Oxidative Medicine and Cellular Longevity·Natalia Robledinos-AntónAntonio Cuadrado
Jun 25, 2020·Cell Communication and Signaling : CCS·Meiling GongCuixia Zheng
Dec 8, 2017·Biomolecules & Therapeutics·Byung-Jin JungSang-Min Jeon
May 28, 2019·International Journal of Molecular Sciences·Angelo SparaneoLucia Anna Muscarella
May 18, 2019·Oxidative Medicine and Cellular Longevity·Emiliano Panieri, Luciano Saso
Feb 15, 2019·Cancer Research·Erica W CloerMichael B Major
Jan 7, 2021·Antioxidants & Redox Signaling·Emiliano Panieri, Luciano Saso
Nov 8, 2019·Seminars in Cancer Biology·Ramanathan KaruppasamyDaisuke Kihara
Oct 21, 2020·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Anju SinghGeorgia Hatzivassiliou
Apr 4, 2021·Antioxidants·Giuseppina BarreraStefania Pizzimenti
Jul 11, 2021·Cellular Oncology (Dordrecht)·Michelle van der MerweAnna-Mart Engelbrecht
Aug 7, 2021·Cellular Signalling·Chorlada PaiboonrungruangXiaoxin Chen
Nov 18, 2018·Journal of Medicinal Chemistry·Zheng-Yu JiangQi-Dong You
Feb 24, 2021·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Derek LeeCarmen Chak-Lui Wong
Aug 28, 2021·Cells·Miriam Sánchez-OrtegaAntonio Garrido
Jun 24, 2021·Molecular Cancer Therapeutics·Di ZhangKaren T Liby
Jan 7, 2022·Clinical & Translational Oncology : Official Publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico·L K KadianS S Chauhan

❮ Previous
Next ❯

Related Concepts

Related Feeds

Birth Defects

Birth defects encompass structural and functional alterations that occur during embryonic or fetal development and are present since birth. The cause may be genetic, environmental or unknown and can result in physical and/or mental impairment. Here is the latest research on birth defects.