Research ArticleCancer

A precision therapy against cancers driven by KIT/PDGFRA mutations

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Science Translational Medicine  01 Nov 2017:
Vol. 9, Issue 414, eaao1690
DOI: 10.1126/scitranslmed.aao1690

Treatment makes tumors feel BLU

Mutations in receptor tyrosine kinases are common in cancer, and a variety of kinase mutations can have oncogenic effects. Not all of these mutations are susceptible to existing kinase inhibitors, and many inhibitors are nonspecific, resulting in undesirable off-target effects. Evans et al. developed BLU-285, an inhibitor that specifically targets the KIT and PDGFRA oncogenic kinases. The authors showed that the compound is very specific for its targets, can inhibit them in the presence of multiple oncogenic mutations, and is selective for the mutant forms of the kinases relative to the wild type. In addition to biochemical and preclinical testing of BLU-285, the authors conducted a phase 1 study, which showed evidence of the compound’s activity in human cancer patients.


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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