دورية أكاديمية
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Systematic Kinase Inhibitor Profiling Identifies CDK9 as a Synthetic Lethal Target in NUT Midline Carcinoma.

التفاصيل البيبلوغرافية
العنوان: Systematic Kinase Inhibitor Profiling Identifies CDK9 as a Synthetic Lethal Target in NUT Midline Carcinoma.
المؤلفون: Brägelmann J; Molecular Pathology, Institute of Pathology, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany; Department of Translational Genomics, Medical Faculty, University of Cologne, Weyertal 115b, 50931 Cologne, Germany., Dammert MA; Molecular Pathology, Institute of Pathology, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany; Department of Translational Genomics, Medical Faculty, University of Cologne, Weyertal 115b, 50931 Cologne, Germany., Dietlein F; Department I of Internal Medicine and Center for Integrated Oncology, University Hospital of Cologne, Kerpener Str. 62, 50937 Cologne, Germany., Heuckmann JM; NEO New Oncology GmbH, Gottfried-Hagen-Str. 20, 51105 Cologne, Germany., Choidas A; Lead Discovery Center (LDC) GmbH, Otto-Hahn-Str. 15, 44227 Dortmund, Germany., Böhm S; Molecular Pathology, Institute of Pathology, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany; Department of Translational Genomics, Medical Faculty, University of Cologne, Weyertal 115b, 50931 Cologne, Germany., Richters A; Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Str. 4a, 44221 Dortmund, Germany., Basu D; Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Str. 4a, 44221 Dortmund, Germany., Tischler V; Department of Translational Genomics, Medical Faculty, University of Cologne, Weyertal 115b, 50931 Cologne, Germany., Lorenz C; Molecular Pathology, Institute of Pathology, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany; Department of Translational Genomics, Medical Faculty, University of Cologne, Weyertal 115b, 50931 Cologne, Germany., Habenberger P; Lead Discovery Center (LDC) GmbH, Otto-Hahn-Str. 15, 44227 Dortmund, Germany., Fang Z; Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Str. 4a, 44221 Dortmund, Germany., Ortiz-Cuaran S; Department of Translational Genomics, Medical Faculty, University of Cologne, Weyertal 115b, 50931 Cologne, Germany., Leenders F; Department of Translational Genomics, Medical Faculty, University of Cologne, Weyertal 115b, 50931 Cologne, Germany., Eickhoff J; Lead Discovery Center (LDC) GmbH, Otto-Hahn-Str. 15, 44227 Dortmund, Germany., Koch U; Lead Discovery Center (LDC) GmbH, Otto-Hahn-Str. 15, 44227 Dortmund, Germany., Getlik M; Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Str. 4a, 44221 Dortmund, Germany., Termathe M; Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Str. 4a, 44221 Dortmund, Germany., Sallouh M; Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Str. 4a, 44221 Dortmund, Germany., Greff Z; Vichem Chemie Research Ltd., Herman Ottó u. 15, Budapest, Hungary., Varga Z; Vichem Chemie Research Ltd., Herman Ottó u. 15, Budapest, Hungary., Balke-Want H; Department of Translational Genomics, Medical Faculty, University of Cologne, Weyertal 115b, 50931 Cologne, Germany; Department I of Internal Medicine and Center for Integrated Oncology, University Hospital of Cologne, Kerpener Str. 62, 50937 Cologne, Germany., French CA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Peifer M; Department of Translational Genomics, Medical Faculty, University of Cologne, Weyertal 115b, 50931 Cologne, Germany., Reinhardt HC; Department I of Internal Medicine and Center for Integrated Oncology, University Hospital of Cologne, Kerpener Str. 62, 50937 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany., Örfi L; Vichem Chemie Research Ltd., Herman Ottó u. 15, Budapest, Hungary; Department of Pharmaceutical Chemistry, Semmelweis University, Hőgyes E. U.9, Budapest, Hungary., Kéri G; Vichem Chemie Research Ltd., Herman Ottó u. 15, Budapest, Hungary., Ansén S; Department I of Internal Medicine and Center for Integrated Oncology, University Hospital of Cologne, Kerpener Str. 62, 50937 Cologne, Germany., Heukamp LC; Department of Translational Genomics, Medical Faculty, University of Cologne, Weyertal 115b, 50931 Cologne, Germany; Institute of Pathology, Medical Faculty, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany., Büttner R; Institute of Pathology, Medical Faculty, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany., Rauh D; Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Str. 4a, 44221 Dortmund, Germany., Klebl BM; Lead Discovery Center (LDC) GmbH, Otto-Hahn-Str. 15, 44227 Dortmund, Germany., Thomas RK; Department of Translational Genomics, Medical Faculty, University of Cologne, Weyertal 115b, 50931 Cologne, Germany; Institute of Pathology, Medical Faculty, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany; German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany. Electronic address: roman.thomas@uni-koeln.de., Sos ML; Molecular Pathology, Institute of Pathology, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany; Department of Translational Genomics, Medical Faculty, University of Cologne, Weyertal 115b, 50931 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany. Electronic address: martin.sos@uni-koeln.de.
المصدر: Cell reports [Cell Rep] 2017 Sep 19; Vol. 20 (12), pp. 2833-2845.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Cell Press Country of Publication: United States NLM ID: 101573691 Publication Model: Print Cited Medium: Internet ISSN: 2211-1247 (Electronic) NLM ISO Abbreviation: Cell Rep Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [Cambridge, MA] : Cell Press, c 2012-
مواضيع طبية MeSH: Molecular Targeted Therapy*, Neoplasms/*enzymology , Neoplasms/*pathology , Protein Kinase Inhibitors/*pharmacology, Cell Cycle Proteins ; Cell Line, Tumor ; Cyclin T/metabolism ; Cyclin-Dependent Kinase 9/antagonists & inhibitors ; Cyclin-Dependent Kinase 9/metabolism ; HEK293 Cells ; High-Throughput Screening Assays ; Humans ; Neoplasms/genetics ; Nuclear Proteins/antagonists & inhibitors ; Nuclear Proteins/metabolism ; Protein Kinase Inhibitors/chemistry ; RNA Polymerase II/metabolism ; Transcription Elongation, Genetic/drug effects ; Transcription Factors/antagonists & inhibitors ; Transcription Factors/metabolism ; Transcription, Genetic/drug effects
مستخلص: Kinase inhibitors represent the backbone of targeted cancer therapy, yet only a limited number of oncogenic drivers are directly druggable. By interrogating the activity of 1,505 kinase inhibitors, we found that BRD4-NUT-rearranged NUT midline carcinoma (NMC) cells are specifically killed by CDK9 inhibition (CDK9i) and depend on CDK9 and Cyclin-T1 expression. We show that CDK9i leads to robust induction of apoptosis and of markers of DNA damage response in NMC cells. While both CDK9i and bromodomain inhibition over time result in reduced Myc protein expression, only bromodomain inhibition induces cell differentiation and a p21-induced cell-cycle arrest in these cells. Finally, RNA-seq and ChIP-based analyses reveal a BRD4-NUT-specific CDK9i-induced perturbation of transcriptional elongation. Thus, our data provide a mechanistic basis for the genotype-dependent vulnerability of NMC cells to CDK9i that may be of relevance for the development of targeted therapies for NMC patients.
(Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)
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فهرسة مساهمة: Keywords: CDK9 inhibitor; NUT midline carcinoma; high-throughput screen; transcriptional elongation
المشرفين على المادة: 0 (BRD4 protein, human)
0 (Cell Cycle Proteins)
0 (Cyclin T)
0 (Nuclear Proteins)
0 (Protein Kinase Inhibitors)
0 (Transcription Factors)
EC 2.7.11.22 (CDK9 protein, human)
EC 2.7.11.22 (Cyclin-Dependent Kinase 9)
EC 2.7.7.- (RNA Polymerase II)
تواريخ الأحداث: Date Created: 20170921 Date Completed: 20180605 Latest Revision: 20191210
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC5622049
DOI: 10.1016/j.celrep.2017.08.082
PMID: 28930680
قاعدة البيانات: MEDLINE
الوصف
تدمد:2211-1247
DOI:10.1016/j.celrep.2017.08.082