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Chemical Proteomics Identifies Druggable Vulnerabilities in a Genetically Defined Cancer
Open accessAbstract
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.
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“The authors discovered compounds that bind to a ligandable cysteine on the nuclear receptor NR0B1, which is regulated by NRF2, a substrate of KEAP1 (ref.181).”
From Advances in covalent drug discovery (2022) · cites this paper as [181]
In the citing paper
“cysteine reactivity and ligandable sites were mapped in mutant Kelch-like ECH-associated protein 1 (KEAP1) and compared with those in wild-type KEAP1 NSCLC lines.”
From Advances in covalent drug discovery (2022) · cites this paper as [181]
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“We finally observed limited overlap of enantioprobe targets with proteins that demonstrated ligandability in previous chemical proteomic studies using cysteine-26,27 or lysine-reactive28 electrophilic fragments (Fig. 3b)”
From Expedited mapping of the ligandable proteome using fully functionalized enantiomeric probe pairs (2019) · cites this paper as [27]
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Self-citationNRF2 Promotes Tumor Maintenance by Modulating mRNA Translation in Pancreatic Cancer
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Self-citationDAX-1 (NR0B1) and steroidogenic factor-1 (SF-1, NR5A1) in human disease
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“The liganded cysteine in NR0B1, C274, is located within a conserved repression helix that commonly possesses an LXXLL sequence in other nuclear receptors but, in NR0B1, has been replaced by a PCFXXLP sequence, where the ‘‘C’’ is C274 (Sablin et al., 2008).”
InfluentialA Small Molecule Inhibits Deregulated NRF2 Transcriptional Activity in Cancer
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“Moreover, to date, only a handful of early-stage small molecules have been identified that inhibit NRF2 function (Bollong et al., 2015; Singh et al., 2016), and, as a consequence, oncogenic mutations in the KEAP1-NRF2 complex remain unactionable from a therapeutic perspective.”
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“NR0B1 and AKR1B10 have been shown to be important for the proliferation of certain cancers (Garcı́a-Aragoncillo et al., 2008; Kinsey et al., 2009; Oda et al., 2009; Wang et al., 2009), including KEAP1mutant NSCLC cells (Oda et al., 2009; Wang et al., 2009).”
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E3 Ubiquitin Ligase RNF31 Cooperates with DAX-1 in Transcriptional Repression of Steroidogenesis
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“NR0B1 has been shown to display a short half-life in other cell systems (Ehrlund et al., 2009), suggesting that this property is an intrinsic feature of the protein.”
Tumorigenic Role of Orphan Nuclear Receptor NR0B1 in Lung Adenocarcinoma
Oda, T., Tian, T., Inoue, M., Ikeda, J., Qiu, Y., Okumura, M., Aozasa, K., & Morii, E. (2009) · American Journal Of Pathology · doi:10.2353/ajpath.2009.090010 · Cited by 36 · cited 3×
“NR0B1 and AKR1B10 have been shown to be important for the proliferation of certain cancers (Garcı́a-Aragoncillo et al., 2008; Kinsey et al., 2009; Oda et al., 2009; Wang et al., 2009), including KEAP1mutant NSCLC cells (Oda et al., 2009; Wang et al., 2009).”
Bruton's tyrosine kinase as a drug discovery target
Pan, Z. (2008) · Drug News & Perspectives · doi:10.1358/dnp.2008.21.7.1255308 · Cited by 30 · cited 2×
“…2010; Liu et al., 2013) and therapeutic agents, including ibrutinib, which targets Bruton’s tyrosine kinase (BTK) for the treatment of B cell cancers (Pan, 2008), and afatinib and AZD9291, which target mutant forms of epidermal growth factor receptor (EGFR) for the treatment of lung cancer…”
Rostovtsev, V. V., Green, L. G., Fokin, V. V., & Sharpless, K. B. (2002) · Angewandte Chemie International Edition · doi:10.1002/1521-3773(20020715)41:14
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The KEAP1-NRF2 system: a thiol-based sensor-effector apparatus for maintaining redox homeostasis
Yamamoto, M., Kensler, T. W., & Motohashi, H. (2018) · Physiological Reviews · doi:10.1152/physrev.00023.2017 · Cited by 1,968
Cancer metabolism: looking forward
Martínez‐Reyes, I., & Chandel, N. S. (2021) · Nature reviews. Cancer · doi:10.1038/s41568-021-00378-6 · Cited by 1,877
Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases
Cuadrado, A., Rojo, A. I., Wells, G., Hayes, J. D., Cousin, S. P., Rumsey, W. L., Attucks, O. C., Franklin, S., Levonen, A., Kensler, T. W., et al. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-018-0008-x · Cited by 1,510
The molecular landscape of head and neck cancer
Leemans, C. R., Snijders, P. J. F., & Brakenhoff, R. H. (2018) · Nature reviews. Cancer · doi:10.1038/nrc.2018.11 · Cited by 1,457
Advances in covalent drug discovery
Boike, L., Henning, N. J., & Nomura, D. K. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00542-z · Cited by 823
Metadata
- Authors
- Bar-Peled, L., Kemper, E. K., Suciu, R. M., Vinogradova, E. V., Backus, K. M., Horning, B. D., Paul, T. A., Ichu, T.-A., Svensson, R. U., Olucha, J., Chang, M. W., Kok, B. P., Zhu, Z., Ihle, N. T., Dix, M. M., Jiang, P., Hayward, M. M., Saez, E., Shaw, R. J., & Cravatt, B. F.
- Affiliations
- Scripps Research Institute (US)
- Pfizer (United States) (US)
- Salk Institute for Biological Studies (US)
- University of California San Diego (US)
- Corresponding author
- Cravatt, Benjamin F.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2017-10
- Volume
- 171
- Issue
- 3
- Pages
- 696-709.e23
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5728659
- OpenAlex
- W2757007104
- Cited by
- 262
- References
- 59
- Citations by year
- 2026: 12 · 2025: 28 · 2024: 34 · 2023: 41 · 2022: 29 · 2021: 30 · 2020: 25 · 2019: 36 · 2018: 24 · 2017: 3
- FWCI
- 9.83
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- NIH (CA087660, CA132630, CA172229, CA215249-01, CA211526)
- NIH-NCI CCSG (P30 014195)
- Chapman Foundation
- Helmsley Charitable Trust
- Damon Runyon Cancer Research Foundation
- American Cancer Society
- Life Sciences Research Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- Nrf2, KEAP1 mutation, non-small cell lung cancer, NR0B1, orphan nuclear receptor, chemoproteomics, druggable vulnerabilities, covalent inhibitors, anchorage-independent growth, transcriptional regulation, antioxidant response
- MeSH terms
- Kelch-Like ECH-Associated Protein 1, Carcinoma, Non-Small-Cell Lung, Cysteine, Humans, Ligands, Lung Neoplasms, Proteome, Cell Line, Tumor, Gene Regulatory Networks, DAX-1 Orphan Nuclear Receptor, Transcriptome
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