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Sci Transl Med. 2017 Jun 14;9(394). pii: eaah6144. doi: 10.1126/scitranslmed.aah6144.

Drugging the catalytically inactive state of RET kinase in RET-rearranged tumors.

Author information

1
Molecular Pathology, Institute of Pathology, Center of Integrated Oncology, University Hospital Cologne, 50937 Cologne, Germany.
2
Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
3
Structural Biology Laboratory, Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
4
Faculty of Chemistry and Chemical Biology, TU Dortmund University, 44227 Dortmund, Germany.
5
Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V., Dortmund, Germany.
6
Institute of Pathology, Center of Integrated Oncology, University Hospital Cologne, 50937 Cologne, Germany.
7
Crown BioScience, Inc., 3375 Scott Blvd, Suite 108, Santa Clara, CA 95054, USA.
8
NEO New Oncology GmbH, 51105 Cologne, Germany.
9
Department of Internal Medicine, Center for Integrated Oncology Köln Bonn, University Hospital Cologne, Cologne, 50931 Cologne, Germany.
10
Cancer Center, Lucerne Cantonal Hospital, 6000 Lucerne, Switzerland.
11
Department of Internal Medicine 5, University Hospital Innsbruck, Haematology/Oncology, Anichstraße 35, 6020 Innsbruck, Austria.
12
VIB-UGent Center for Medical Biotechnology, VIB, B-9000 Ghent, Belgium.
13
Department of Biochemistry, Ghent University, B-9000 Ghent, Belgium.
14
Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
15
Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck College, Malet Street, London WC1E 7HX, UK.
16
German Cancer Consortium (DKTK), partner site Heidelberg, and German Cancer Research Center (DKFZ), Heidelberg, Germany.
17
Molecular Pathology, Institute of Pathology, Center of Integrated Oncology, University Hospital Cologne, 50937 Cologne, Germany. martin.sos@uni-koeln.de.

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.

PMID:
28615362
PMCID:
PMC5805089
DOI:
10.1126/scitranslmed.aah6144
[Indexed for MEDLINE]
Free PMC Article

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