Plenker, Dennis, Riedel, Maximilian, Braegelmann, Johannes, Dammert, Marcel A., Chauhan, Rakhee, Knowles, Phillip P., Lorenz, Carina, Keul, Marina, Buehrmann, Mike, Pagel, Oliver, Tischler, Verena ORCID: 0000-0002-6673-8329, Scheel, Andreas H., Schtte, Daniel, Song, Yanrui, Stark, Justina, Mrugalla, Florian ORCID: 0000-0002-6281-6051, Alber, Yannic, Richters, Andre, Engel, Julian, Leenders, Frauke, Heuckmann, Johannes M., Wolf, Juergen, Diebold, Joachim, Pall, Georg, Peifer, Martin ORCID: 0000-0002-5243-5503, Aerts, Maarten, Gevaert, Kris ORCID: 0000-0002-4237-0283, Zahedi, Rene P., Buettner, Reinhard, Shokat, Kevan M., McDonald, Neil Q., Kast, Stefan M., Gautschi, Oliver, Thomas, Roman K. and Sos, Martin L. (2017). Drugging the catalytically inactive state of RET kinase in RET-rearranged tumors. Sci. Transl. Med., 9 (394). WASHINGTON: AMER ASSOC ADVANCEMENT SCIENCE. ISSN 1946-6242

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Abstract

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Plenker, DennisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Riedel, MaximilianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Braegelmann, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dammert, Marcel A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chauhan, RakheeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Knowles, Phillip P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lorenz, CarinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Keul, MarinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buehrmann, MikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pagel, OliverUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tischler, VerenaUNSPECIFIEDorcid.org/0000-0002-6673-8329UNSPECIFIED
Scheel, Andreas H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schtte, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Song, YanruiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stark, JustinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mrugalla, FlorianUNSPECIFIEDorcid.org/0000-0002-6281-6051UNSPECIFIED
Alber, YannicUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Richters, AndreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Engel, JulianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leenders, FraukeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heuckmann, Johannes M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wolf, JuergenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Diebold, JoachimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pall, GeorgUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peifer, MartinUNSPECIFIEDorcid.org/0000-0002-5243-5503UNSPECIFIED
Aerts, MaartenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gevaert, KrisUNSPECIFIEDorcid.org/0000-0002-4237-0283UNSPECIFIED
Zahedi, Rene P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buettner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shokat, Kevan M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McDonald, Neil Q.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kast, Stefan M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gautschi, OliverUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomas, Roman K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sos, Martin L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-227756
DOI: 10.1126/scitranslmed.aah6144
Journal or Publication Title: Sci. Transl. Med.
Volume: 9
Number: 394
Date: 2017
Publisher: AMER ASSOC ADVANCEMENT SCIENCE
Place of Publication: WASHINGTON
ISSN: 1946-6242
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
IN-VITRO; LUNG ADENOCARCINOMA; OPEN-LABEL; INHIBITOR; RESISTANCE; FUSIONS; DISCOVERY; GENE; ALK; PHOSPHORYLATIONMultiple languages
Cell Biology; Medicine, Research & ExperimentalMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/22775

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