Drugging the catalytically inactive state of RET kinase in RET-rearranged tumors
| Autor: | Neil Q. McDonald, Kris Gevaert, Dennis Plenker, René P. Zahedi, Georg Pall, Mike Bührmann, Johannes M. Heuckmann, Reinhard Buettner, Marcel A. Dammert, Daniel Schütte, Phillip P. Knowles, Maarten Aerts, Carina Lorenz, Andreas H. Scheel, Verena Tischler, Joachim Diebold, Justina Stark, Martin L. Sos, Oliver Gautschi, Julian Engel, Florian Mrugalla, Rakhee Chauhan, Johannes Brägelmann, Frauke Leenders, Yannic Alber, Stefan M. Kast, Oliver Pagel, Martin Peifer, Maximilian Riedel, Marina Keul, Kevan M. Shokat, André Richters, Jürgen Wolf, Yanrui Song, Roman K. Thomas |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Genetics congenital hereditary and neonatal diseases and abnormalities endocrine system Mutation endocrine system diseases Kinase Ponatinib Druggability Medullary thyroid cancer General Medicine Gene rearrangement Biology medicine.disease medicine.disease_cause 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology chemistry Proto-Oncogene Proteins c-ret medicine Cancer research Protein kinase A |
| Zdroj: | Science Translational Medicine. 9 |
| ISSN: | 1946-6242 1946-6234 |
| DOI: | 10.1126/scitranslmed.aah6144 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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