2. Academic Validation
  3. A precision therapy against cancers driven by KIT/PDGFRA mutations

A precision therapy against cancers driven by KIT/PDGFRA mutations

  • Sci Transl Med. 2017 Nov 1;9(414):eaao1690. doi: 10.1126/scitranslmed.aao1690.
Erica K Evans 1,  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

Affiliations

  • 1 Blueprint Medicines, Cambridge, MA 02139, USA.
  • 2 Laboratory of Experimental Oncology, Department of Oncology, KU Leuven, Belgium 3000.
  • 3 VA Health Care System and Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA.
  • 4 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 5 Blueprint Medicines, Cambridge, MA 02139, USA. clengauer@blueprintmedicines.com.
PMID: 29093181 DOI: 10.1126/scitranslmed.aao1690
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.

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