6533b82bfe1ef96bd128e39a
RESEARCH PRODUCT
Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor.
James E. BradnerJillian D. CavanaughBrian J. AbrahamHans Skovgaard PoulsenGrit S. Herter-sprieRichard A. YoungNathanael S. GrayJacob B. ReibelNicholas KwiatkowskiFatima Al-shahrourJianming ZhangSigne Regner MichaelsenDavid A. BarbieKwok-kin WongAbigail AltabefPeng GaoMarzia CapellettiRani E. GeorgeYan LiuTinghu ZhangCamilla L. ChristensenAmir Reza ArefJulian CarreteroTakeshi ShimamuraEdmond ChipumuroEsra A. Akbaysubject
Cancer ResearchLung NeoplasmsTranscription GeneticMolecular Sequence DataAntineoplastic AgentsBiologyBioinformaticsArticleMiceSuper-enhancerDownregulation and upregulationCell Line TumorMedicineAnimalsHumansEnzyme InhibitorsneoplasmsTranscription factorRegulation of gene expressionbusiness.industryCell BiologyNeoplasms ExperimentalSequence Analysis DNASmall Cell Lung CarcinomaXenograft Model Antitumor AssayshumanitiesCyclin-Dependent Kinasesrespiratory tract diseasesHigh-Throughput Screening AssaysGene Expression Regulation NeoplasticOncologyCovalent bondCancer cellCancer researchNon small cellSmall Cell Lung CarcinomaCyclin-dependent kinase 7businessTranscription Factor GeneCDK12Transcription Factorsdescription
Small cell lung cancer (SCLC) is an aggressive disease with high mortality, and the identification of effective pharmacological strategies to target SCLC biology represents an urgent need. Using a high-throughput cellular screen of a diverse chemical library, we observe that SCLC is sensitive to transcription-targeting drugs, in particular to THZ1, a recently identified covalent inhibitor of cyclin-dependent kinase 7. We find that expression of super-enhancer-associated transcription factor genes, including MYC family proto-oncogenes and neuroendocrine lineage-specific factors, is highly vulnerability to THZ1 treatment. We propose that downregulation of these transcription factors contributes, in part, to SCLC sensitivity to transcriptional inhibitors and that THZ1 represents a prototype drug for tailored SCLC therapy.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2014-12-01 | Cancer cell |