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Drugging the catalytically inactive state of RET kinase in RET-rearranged tumors.
Plenker, Dennis; Riedel, Maximilian; Brägelmann, Johannes; Dammert, Marcel A; Chauhan, Rakhee; Knowles, Phillip P; Lorenz, Carina; Keul, Marina; Bührmann, Mike; Pagel, Oliver; Tischler, Verena; Scheel, Andreas H; Schütte, Daniel; Song, Yanrui; Stark, Justina; Mrugalla, Florian; Alber, Yannic; Richters, André; Engel, Julian; Leenders, Frauke; Heuckmann, Johannes M; Wolf, Jürgen; Diebold, Joachim; Pall, Georg; Peifer, Martin; Aerts, Maarten; Gevaert, Kris; Zahedi, René P; Buettner, Reinhard; Shokat, Kevan M; McDonald, Neil Q; Kast, Stefan M; Gautschi, Oliver; Thomas, Roman K; Sos, Martin L.
Afiliación
  • Plenker D; Molecular Pathology, Institute of Pathology, Center of Integrated Oncology, University Hospital Cologne, 50937 Cologne, Germany.
  • Riedel M; 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.
  • Dammert MA; Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
  • Chauhan R; Molecular Pathology, Institute of Pathology, Center of Integrated Oncology, University Hospital Cologne, 50937 Cologne, Germany.
  • Knowles PP; Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
  • Lorenz C; Molecular Pathology, Institute of Pathology, Center of Integrated Oncology, University Hospital Cologne, 50937 Cologne, Germany.
  • Keul M; Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
  • Bührmann M; Structural Biology Laboratory, Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
  • Pagel O; Structural Biology Laboratory, Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
  • Tischler V; Molecular Pathology, Institute of Pathology, Center of Integrated Oncology, University Hospital Cologne, 50937 Cologne, Germany.
  • Scheel AH; Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
  • Schütte D; Faculty of Chemistry and Chemical Biology, TU Dortmund University, 44227 Dortmund, Germany.
  • Song Y; Faculty of Chemistry and Chemical Biology, TU Dortmund University, 44227 Dortmund, Germany.
  • Stark J; Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V., Dortmund, Germany.
  • Mrugalla F; Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
  • Alber Y; Institute of Pathology, Center of Integrated Oncology, University Hospital Cologne, 50937 Cologne, Germany.
  • Richters A; Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
  • Engel J; Crown BioScience, Inc., 3375 Scott Blvd, Suite 108, Santa Clara, CA 95054, USA.
  • Leenders F; Faculty of Chemistry and Chemical Biology, TU Dortmund University, 44227 Dortmund, Germany.
  • Heuckmann JM; Faculty of Chemistry and Chemical Biology, TU Dortmund University, 44227 Dortmund, Germany.
  • Wolf J; Faculty of Chemistry and Chemical Biology, TU Dortmund University, 44227 Dortmund, Germany.
  • Diebold J; Faculty of Chemistry and Chemical Biology, TU Dortmund University, 44227 Dortmund, Germany.
  • Pall G; Faculty of Chemistry and Chemical Biology, TU Dortmund University, 44227 Dortmund, Germany.
  • Peifer M; NEO New Oncology GmbH, 51105 Cologne, Germany.
  • Aerts M; NEO New Oncology GmbH, 51105 Cologne, Germany.
  • Gevaert K; Department of Internal Medicine, Center for Integrated Oncology Köln Bonn, University Hospital Cologne, Cologne, 50931 Cologne, Germany.
  • Zahedi RP; Cancer Center, Lucerne Cantonal Hospital, 6000 Lucerne, Switzerland.
  • Buettner R; Department of Internal Medicine 5, University Hospital Innsbruck, Haematology/Oncology, Anichstraße 35, 6020 Innsbruck, Austria.
  • Shokat KM; Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
  • McDonald NQ; VIB-UGent Center for Medical Biotechnology, VIB, B-9000 Ghent, Belgium.
  • Kast SM; Department of Biochemistry, Ghent University, B-9000 Ghent, Belgium.
  • Gautschi O; VIB-UGent Center for Medical Biotechnology, VIB, B-9000 Ghent, Belgium.
  • Thomas RK; Department of Biochemistry, Ghent University, B-9000 Ghent, Belgium.
  • Sos ML; Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V., Dortmund, Germany.
Sci Transl Med ; 9(394)2017 06 14.
Article en En | MEDLINE | ID: mdl-28615362
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-RETI788N 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.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Reordenamiento Génico / Adenocarcinoma / Inhibidores de Proteínas Quinasas / Proteínas Proto-Oncogénicas c-ret / Neoplasias Pulmonares Límite: Animals / Humans Idioma: En Revista: Sci Transl Med Asunto de la revista: CIENCIA / MEDICINA Año: 2017 Tipo del documento: Article País de afiliación: Alemania

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Reordenamiento Génico / Adenocarcinoma / Inhibidores de Proteínas Quinasas / Proteínas Proto-Oncogénicas c-ret / Neoplasias Pulmonares Límite: Animals / Humans Idioma: En Revista: Sci Transl Med Asunto de la revista: CIENCIA / MEDICINA Año: 2017 Tipo del documento: Article País de afiliación: Alemania