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
  • 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. [email protected].
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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