دورية أكاديمية
Drugging the catalytically inactive state of RET kinase in RET-rearranged tumors.
| العنوان: | Drugging the catalytically inactive state of RET kinase in RET-rearranged tumors. |
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| المؤلفون: | Plenker D; Molecular Pathology, Institute of Pathology, Center of Integrated Oncology, University Hospital Cologne, 50937 Cologne, Germany.; Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany., Riedel M; Molecular Pathology, Institute of Pathology, Center of Integrated Oncology, University Hospital Cologne, 50937 Cologne, Germany.; Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany., Brägelmann J; Molecular Pathology, Institute of Pathology, Center of Integrated Oncology, University Hospital Cologne, 50937 Cologne, Germany.; Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany., Dammert MA; Molecular Pathology, Institute of Pathology, Center of Integrated Oncology, University Hospital Cologne, 50937 Cologne, Germany.; Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany., Chauhan R; Structural Biology Laboratory, Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK., Knowles PP; Structural Biology Laboratory, Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK., Lorenz C; Molecular Pathology, Institute of Pathology, Center of Integrated Oncology, University Hospital Cologne, 50937 Cologne, Germany.; Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany., Keul M; Faculty of Chemistry and Chemical Biology, TU Dortmund University, 44227 Dortmund, Germany., Bührmann M; Faculty of Chemistry and Chemical Biology, TU Dortmund University, 44227 Dortmund, Germany., Pagel O; Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V., Dortmund, Germany., Tischler V; Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany., Scheel AH; Institute of Pathology, Center of Integrated Oncology, University Hospital Cologne, 50937 Cologne, Germany., Schütte D; Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany., Song Y; Crown BioScience, Inc., 3375 Scott Blvd, Suite 108, Santa Clara, CA 95054, USA., Stark J; Faculty of Chemistry and Chemical Biology, TU Dortmund University, 44227 Dortmund, Germany., Mrugalla F; Faculty of Chemistry and Chemical Biology, TU Dortmund University, 44227 Dortmund, Germany., Alber Y; Faculty of Chemistry and Chemical Biology, TU Dortmund University, 44227 Dortmund, Germany., Richters A; Faculty of Chemistry and Chemical Biology, TU Dortmund University, 44227 Dortmund, Germany., Engel J; Faculty of Chemistry and Chemical Biology, TU Dortmund University, 44227 Dortmund, Germany., Leenders F; NEO New Oncology GmbH, 51105 Cologne, Germany., Heuckmann JM; NEO New Oncology GmbH, 51105 Cologne, Germany., Wolf J; Department of Internal Medicine, Center for Integrated Oncology Köln Bonn, University Hospital Cologne, Cologne, 50931 Cologne, Germany., Diebold J; Cancer Center, Lucerne Cantonal Hospital, 6000 Lucerne, Switzerland., Pall G; Department of Internal Medicine 5, University Hospital Innsbruck, Haematology/Oncology, Anichstraße 35, 6020 Innsbruck, Austria., Peifer M; Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany., Aerts M; VIB-UGent Center for Medical Biotechnology, VIB, B-9000 Ghent, Belgium.; Department of Biochemistry, Ghent University, B-9000 Ghent, Belgium., Gevaert K; VIB-UGent Center for Medical Biotechnology, VIB, B-9000 Ghent, Belgium.; Department of Biochemistry, Ghent University, B-9000 Ghent, Belgium., Zahedi RP; Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V., Dortmund, Germany., Buettner R; Institute of Pathology, Center of Integrated Oncology, University Hospital Cologne, 50937 Cologne, Germany., Shokat KM; Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA., McDonald NQ; Structural Biology Laboratory, Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.; Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck College, Malet Street, London WC1E 7HX, UK., Kast SM; Faculty of Chemistry and Chemical Biology, TU Dortmund University, 44227 Dortmund, Germany., Gautschi O; Cancer Center, Lucerne Cantonal Hospital, 6000 Lucerne, Switzerland., Thomas RK; Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany.; Department of Internal Medicine, Center for Integrated Oncology Köln Bonn, University Hospital Cologne, Cologne, 50931 Cologne, Germany.; German Cancer Consortium (DKTK), partner site Heidelberg, and German Cancer Research Center (DKFZ), Heidelberg, Germany., Sos ML; Molecular Pathology, Institute of Pathology, Center of Integrated Oncology, University Hospital Cologne, 50937 Cologne, Germany. martin.sos@uni-koeln.de.; Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany. |
| المصدر: | Science translational medicine [Sci Transl Med] 2017 Jun 14; Vol. 9 (394). |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101505086 Publication Model: Print Cited Medium: Internet ISSN: 1946-6242 (Electronic) Linking ISSN: 19466234 NLM ISO Abbreviation: Sci Transl Med Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, DC : American Association for the Advancement of Science |
| مواضيع طبية MeSH: | Adenocarcinoma/*metabolism , Gene Rearrangement/*genetics , Lung Neoplasms/*metabolism , Protein Kinase Inhibitors/*pharmacology , Proto-Oncogene Proteins c-ret/*genetics, Adenocarcinoma of Lung ; Animals ; Cell Line, Tumor ; Cytoskeletal Proteins/genetics ; Drug Resistance, Neoplasm/genetics ; Gene Rearrangement/drug effects ; Heterocyclic Compounds, 4 or More Rings/pharmacology ; Humans ; Imidazoles/pharmacology ; Mice ; Mutation ; NIH 3T3 Cells ; Pyridazines/pharmacology |
| مستخلص: | Oncogenic fusion events have been identified in a broad range of tumors. Among them, RET rearrangements represent distinct and potentially druggable targets that are recurrently found in lung adenocarcinomas. We provide further evidence that current anti-RET drugs may not be potent enough to induce durable responses in such tumors. We report that potent inhibitors, such as AD80 or ponatinib, that stably bind in the DFG-out conformation of RET may overcome these limitations and selectively kill RET -rearranged tumors. Using chemical genomics in conjunction with phosphoproteomic analyses in RET -rearranged cells, we identify the CCDC6-RET I788N mutation and drug-induced mitogen-activated protein kinase pathway reactivation as possible mechanisms by which tumors may escape the activity of RET inhibitors. Our data provide mechanistic insight into the druggability of RET kinase fusions that may be of help for the development of effective therapies targeting such tumors. (Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.) |
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| معلومات مُعتمدة: | FC001115 United Kingdom CRUK_ Cancer Research UK; United Kingdom MRC_ Medical Research Council; FC001115 United Kingdom ARC_ Arthritis Research UK; United Kingdom WT_ Wellcome Trust; R01 CA197178 United States CA NCI NIH HHS |
| المشرفين على المادة: | 0 (AD80 compound) 0 (CCDC6 protein, human) 0 (Cytoskeletal Proteins) 0 (Heterocyclic Compounds, 4 or More Rings) 0 (Imidazoles) 0 (Protein Kinase Inhibitors) 0 (Pyridazines) 4340891KFS (ponatinib) EC 2.7.10.1 (Proto-Oncogene Proteins c-ret) |
| تواريخ الأحداث: | Date Created: 20170616 Date Completed: 20180319 Latest Revision: 20240610 |
| رمز التحديث: | 20240610 |
| مُعرف محوري في PubMed: | PMC5805089 |
| DOI: | 10.1126/scitranslmed.aah6144 |
| PMID: | 28615362 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1946-6242 |
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| DOI: | 10.1126/scitranslmed.aah6144 |