Research ArticleCancer

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

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Science Translational Medicine  14 Jun 2017:
Vol. 9, Issue 394, eaah6144
DOI: 10.1126/scitranslmed.aah6144

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RET-ting out lung tumors

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.