Abstract：
:The transcription factor NRF2 is a master regulator of the cellular antioxidant response, and it is often genetically activated in non-small-cell lung cancers (NSCLCs) by, for instance, mutations in the negative regulator KEAP1. While direct pharmacological inhibition of NRF2 has proven challenging, its aberrant activation rewires biochemical networks in cancer cells that may create special vulnerabilities. Here, we use chemical proteomics to map druggable proteins that are selectively expressed in KEAP1-mutant NSCLC cells. Principal among these is NR0B1, an atypical orphan nuclear receptor that we show engages in a multimeric protein complex to regulate the transcriptional output of KEAP1-mutant NSCLC cells. We further identify small molecules that covalently target a conserved cysteine within the NR0B1 protein interaction domain, and we demonstrate that these compounds disrupt NR0B1 complexes and impair the anchorage-independent growth of KEAP1-mutant cancer cells. Our findings designate NR0B1 as a druggable transcriptional regulator that supports NRF2-dependent lung cancers.
journal_name
Celljournal_title
Cellauthors
Bar-Peled L,Kemper EK,Suciu RM,Vinogradova EV,Backus KM,Horning BD,Paul TA,Ichu TA,Svensson RU,Olucha J,Chang MW,Kok BP,Zhu Z,Ihle NT,Dix MM,Jiang P,Hayward MM,Saez E,Shaw RJ,Cravatt BFdoi
10.1016/j.cell.2017.08.051subject
Has Abstractpub_date
2017-10-19 00:00:00pages
696-709.e23issue
3eissn
0092-8674issn
1097-4172pii
S0092-8674(17)31047-4journal_volume
171pub_type
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