A precision therapy against cancers driven by KIT/PDGFRA mutations

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

    Research output: Contribution to journalArticle

    44 Scopus citations


    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.

    Original languageEnglish (US)
    Article numbereaao1690
    JournalScience translational medicine
    Issue number414
    StatePublished - Nov 1 2017

    ASJC Scopus subject areas

    • Medicine(all)

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    Evans, E. K., Gardino, A. K., Kim, J. L., Hodous, B. L., Shutes, A., Davis, A., Zhu, X. J., Schmidt-Kittler, O., Wilson, D., Wilson, K., DiPietro, L., Zhang, Y., Brooijmans, N., LaBranche, T. P., Wozniak, A., Gebreyohannes, Y. K., Schöffski, P., Heinrich, M. C., DeAngelo, D. J., ... Lengauer, C. (2017). A precision therapy against cancers driven by KIT/PDGFRA mutations. Science translational medicine, 9(414), [eaao1690]. https://doi.org/10.1126/scitranslmed.aao1690