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.