Chemical Proteomics Identifies Druggable Vulnerabilities in a Genetically Defined Cancer
| Autor: | Ping Jiang, Enrique Saez, Benjamin D. Horning, Radu M. Suciu, Esther K. Kemper, Thomas A Paul, Keriann M. Backus, Jose Olucha, Liron Bar-Peled, Melissa M. Dix, Reuben J. Shaw, Taka-Aki Ichu, Matthew Merrill Hayward, Bernard P. Kok, Ekaterina V. Vinogradova, Nathan T. Ihle, Zhou Zhu, Max W. Chang, Robert U. Svensson, Benjamin F. Cravatt |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Lung Neoplasms Proteome Druggability Computational biology Biology Ligands Bioinformatics Proteomics Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences 0302 clinical medicine Carcinoma Non-Small-Cell Lung Cell Line Tumor medicine Transcriptional regulation Humans Gene Regulatory Networks Cysteine Transcription factor Kelch-Like ECH-Associated Protein 1 DAX-1 Orphan Nuclear Receptor Cancer medicine.disease KEAP1 030104 developmental biology Nuclear receptor 030220 oncology & carcinogenesis Cancer cell Transcriptome |
| Zdroj: | Cell. 171:696-709.e23 |
| ISSN: | 0092-8674 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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