RT Journal Article
SR Electronic
T1 Drugging the catalytically inactive state of RET kinase in RET-rearranged tumors
JF Science Translational Medicine
FD American Association for the Advancement of Science
SP eaah6144
DO 10.1126/scitranslmed.aah6144
VO 9
IS 394
A1 Plenker, Dennis
A1 Riedel, Maximilian
A1 Brägelmann, Johannes
A1 Dammert, Marcel A.
A1 Chauhan, Rakhee
A1 Knowles, Phillip P.
A1 Lorenz, Carina
A1 Keul, Marina
A1 Bührmann, Mike
A1 Pagel, Oliver
A1 Tischler, Verena
A1 Scheel, Andreas H.
A1 Schütte, Daniel
A1 Song, Yanrui
A1 Stark, Justina
A1 Mrugalla, Florian
A1 Alber, Yannic
A1 Richters, André
A1 Engel, Julian
A1 Leenders, Frauke
A1 Heuckmann, Johannes M.
A1 Wolf, Jürgen
A1 Diebold, Joachim
A1 Pall, Georg
A1 Peifer, Martin
A1 Aerts, Maarten
A1 Gevaert, Kris
A1 Zahedi, René P.
A1 Buettner, Reinhard
A1 Shokat, Kevan M.
A1 McDonald, Neil Q.
A1 Kast, Stefan M.
A1 Gautschi, Oliver
A1 Thomas, Roman K.
A1 Sos, Martin L.
YR 2017
UL http://stm.sciencemag.org/content/9/394/eaah6144.abstract
AB Gene fusions and rearrangements serve as oncogenic drivers in a number of tumor types, and some of these can be targeted with existing drugs. RET rearrangements have been identified as drivers in some lung adenocarcinomas, but previous attempts to target RET have not been successful. Plenker et al. determined why the drugs previously proposed for inhibiting RET were not sufficiently potent and showed that successful inhibition of RET requires the ability to bind RET in its catalytically inactive conformation, known as the “DFG-out conformation,” thus locking it in an inactive state. The authors also identified drugs that bind RET in the desired conformation and demonstrated their efficacy in patient-derived xenograft models.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.