Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 9, Issue 394, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aah6144
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Funding
- German federal state North Rhine Westphalia
- European Union (European Regional Development Fund: Investing In Your Future) as part of the PerMed
- NRW initiative [005-1111-0025]
- EFRE initiative [LS-1-1-030]
- German Ministry of Science and Education (BMBF) as part of the e:Med program [01ZX1303, 01ZX1603, 01ZX1406]
- Deutsche Forschungsgemeinschaft [TH1386/3-1, KA1381/5-1]
- German Consortium for Translational Cancer Research (DKTK) Joint Funding program
- European Respiratory Society/European Molecular Biology Organization Long-Term Research fellowship [LTRF 2014-2951]
- Francis Crick Institute
- Cancer Research UK [FC001115]
- UK Medical Research Council [FC001115]
- Wellcome Trust [FC001115]
- NCI/NIH [5R01CA197178]
- Association for Multiple Endocrine Neoplasia Disorders MTC Research Fund
- Ministerium fur Innovation, Wissenschaft und Forschung des Landes Nordrhein-Westfalen
- Senatsverwaltung fur Wirtschaft, Technologie und Forschung des Landes Berlin
- Bundesministerium fur Bildung und Forschung
- The Francis Crick Institute [10115, 10332, 10461] Funding Source: researchfish
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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.
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