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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.

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.

journal_name

Oncogene

journal_title

Oncogene

authors

Choi EJ,Jung BJ,Lee SH,Yoo HS,Shin EA,Ko HJ,Chang S,Kim SY,Jeon SM

doi

10.1038/onc.2017.153

subject

Has Abstract

pub_date

2017-09-14 00:00:00

pages

5285-5295

issue

37

eissn

0950-9232

issn

1476-5594

pii

onc2017153

journal_volume

36

pub_type

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