Drugging the catalytically inactive state of RET kinase in RET-rearranged tumors
Plenker, D. and Riedel, M. and Brägelmann, J. and Dammert, M.A. and Chauhan, R. and Knowles, P.P. and Lorenz, C. and Keul, M. and Bührmann, M. and Pagel, O. and Tischler, V. and Scheel, A.H. and Schütte, D. and Song, Y. and Stark, J. and Mrugalla, F. and Alber, Y. and Richters, A. and Engel, J. and Leenders, F. and Heuckmann, J.M. and Wolf, J. and Diebold, J. and Pall, G. and Peifer, M. and Aerts, M. and Gevaert, K. and Zahedi, R.P. and Buettner, R. and Shokat, K.M. and Mcdonald, N.Q. and Kast, S.M. and Gautschi, O. and Thomas, R.K. and Sos, M.L.
SCIENCE TRANSLATIONAL MEDICINE
Volume: 9 Pages:
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.