A precision therapy against cancers driven by KIT/PDGFRA mutations - PubMed (original) (raw)

Clinical Trial

. 2017 Nov 1;9(414):eaao1690.

doi: 10.1126/scitranslmed.aao1690.

Alexandra K Gardino 1, Joseph L Kim 1, Brian L Hodous 1, Adam Shutes 1, Alison Davis 1, Xing Julia Zhu 1, Oleg Schmidt-Kittler 1, Doug Wilson 1, Kevin Wilson 1, Lucian DiPietro 1, Yulian Zhang 1, Natasja Brooijmans 1, Timothy P LaBranche 1, Agnieszka Wozniak 2, Yemarshet K Gebreyohannes 2, Patrick Schöffski 2, Michael C Heinrich 3, Daniel J DeAngelo 4, Stephen Miller 1, Beni Wolf 1, Nancy Kohl 1, Timothy Guzi 1, Nicholas Lydon 1, Andy Boral 1, Christoph Lengauer 5

Affiliations

Clinical Trial

A precision therapy against cancers driven by KIT/PDGFRA mutations

Erica K Evans et al. Sci Transl Med. 2017.

Abstract

Targeting oncogenic kinase drivers with small-molecule inhibitors can have marked therapeutic benefit, especially when administered to an appropriate genomically defined patient population. Cancer genomics and mechanistic studies have revealed that heterogeneous mutations within a single kinase can result in various mechanisms of kinase activation. Therapeutic benefit to patients can best be optimized through an in-depth understanding of the disease-driving mutations combined with the ability to match these insights to tailored highly selective drugs. This rationale is presented for BLU-285, a clinical stage inhibitor of oncogenic KIT and PDGFRA alterations, including activation loop mutants that are ineffectively treated by current therapies. BLU-285, designed to preferentially interact with the active conformation of KIT and PDGFRA, potently inhibits activation loop mutants KIT D816V and PDGFRA D842V with subnanomolar potency and also inhibits other well-characterized disease-driving KIT mutants both in vitro and in vivo in preclinical models. Early clinical evaluation of BLU-285 in a phase 1 study has demonstrated marked activity in patients with diseases associated with KIT (aggressive systemic mastocytosis and gastrointestinal stromal tumor) and PDGFRA (gastrointestinal stromal tumor) activation loop mutations.

Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

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