Research ArticleCancer

A precision therapy against cancers driven by KIT/PDGFRA mutations

See allHide authors and affiliations

Science Translational Medicine  01 Nov 2017:
Vol. 9, Issue 414, eaao1690
DOI: 10.1126/scitranslmed.aao1690
  • Fig. 1. Inhibitor binding analysis reveals type I preference for KIT activation loop mutants.

    Half-maximal inhibitory concentration (IC50; in nanomolar) of type I (15 for KIT WT and 26 for mutant KIT) and 18 type II compounds bound to various KIT proteins as measured by LanthaScreen in the absence of ATP. Median values are depicted by horizontal lines. Reference compounds are depicted as follows: imatinib, red triangle; sunitinib, green triangle; regorafenib, blue triangle; crenolanib, purple circle.

  • Fig. 2. BLU-285 is a potent and highly selective inhibitor of KIT and PDGFRA activation loop mutants.

    (A) Chemical structure of BLU-285. (B) Biochemical potency against KIT WT and the KIT del557-558 (exon 11), D816V (exon 17), and PDGFRA D842V (exon 18) mutants for BLU-285 and several compounds in use or being explored for the treatment of GIST and SM. (C) Binding data for compounds screened at 3 μM against 392 kinases are depicted as red circles on the kinome tree. The size of the circle indicates binding potency. Kinome illustration reproduced courtesy of Cell Signaling Technology (www.cellsignal.com).

  • Fig. 3. BLU-285 is active against a spectrum of KIT and PDGFRA disease-relevant mutants.

    Biochemical data highlights BLU-285 activity across 19 KIT and PDGFRA mutant proteins. Data are depicted as bars that represent the mean IC50 value + SD for BLU-285 (light blue) and imatinib (black). Clinically observed KIT and PDGFRA mutants are clustered by their location within the primary protein sequence. The exon location and associated structural region for each mutant are listed above, and disease relevant mutants are shown in bold.

  • Fig. 4. BLU-285 demonstrates antitumor activity across multiple KIT-driven in vivo disease models.

    BLU-285 antitumor activity in both primary and refractory KIT-driven disease models. (A to C) Antitumor activity (A), body weight (B), and PK/PD (C) relationship for BLU-285 and dasatinib in a P815 KIT D814Y mastocytoma allograft model. (D to F) Antitumor activity of BLU-285 and reference compounds (top) and pharmacodynamic analysis of KIT inhibition (bottom) in human GIST PDX models of disease with (D) KIT exon 11/17 delW557K558/Y823D, (E) KIT exon 11 delW557-V559insF, and (F) KIT exon 11/13 delW557K558/V654A mutations. QD, once daily; BID, twice daily.

  • Fig. 5. Clinical data with BLU-285 confirm early evidence of activity in patients with diseases driven by KIT and PDGFRA activation loop mutations.

    (A) BLU-285 [30 mg per os (PO), QD] induces rapid radiographic clinical response per RECIST1.1 (31% tumor reduction at week 8) and decline in PDGFRA D842V ctDNA in a patient with PDGFRA D842V–mutant GIST that progressed on previous imatinib, dasatinib, and crenolanib therapy. The images show CT scans with tumor circled in yellow. The graph shows tumor burden as measured by the sum of the longest dimension for the target lesions (per RECIST1.1) and mutant allele frequency (MAF). (B) Radiographic clinical response per RECIST1.1 with BLU-285 (60 mg PO, QD) in a patient with primary KIT D820Y–mutant GIST that had previously progressed on imatinib, sunitinib, and regorafenib. The images show CT scans with a pelvic tumor mass highlighted within yellow circles that demonstrated a 28% tumor reduction at day 1 of cycle 5. A partial response of 32% tumor reduction was confirmed by central radiographic review at cycle 15. (C) BLU-285 (30 mg PO, QD) markedly decreased bone marrow mast cell burden in a patient with KIT D816V–driven aggressive SM. At baseline, diffuse bone marrow infiltration with malignant mast cells obliterated normal hematopoiesis (left). After BLU-285 treatment, there was a marked reduction in malignant mast cells and return of normal trilineage hematopoiesis (right). Scale bars, 1000 μm (left) and 200 μm (right).

  • Table 1. Inhibition of KIT/PDGFRA autophosphorylation and proliferation in cell lines.
    pKIT inhibition IC50 (nM)
    Cell lineMutationExonTissueBLU-285ImatinibSunitinibRegorafenib
    M-07eKIT WTHuman megakaryoblastic leukemia192336363
    HMC1.1KIT V560G11Human mast cell leukemia10021138
    KasumiKIT N822K17Human acute myeloid leukemia401296111
    P815KIT D816Y17Murine mastocytoma221236611128
    HMC1.2KIT V560G/D816V11/17Human mast cell leukemia4914414,488314
    CHOPDGFRA WTEngineered95<100
    CHOPDGFRA V561D12Engineered40<100
    CHOPDGFRA D842V18Engineered303145
    Proliferation IC50 (nM)
    Cell lineKIT mutationExonTissueBLU-285ImatinibSunitinibRegorafenib
    M-07eWTHuman megakaryoblastic leukemia417604132678
    HMC1.1V560G11Human mast cell leukemia3443613115
    KasumiN822K17Human acute myeloid leukemia7538231211
    P815D816Y17Murine mastocytoma2022,8112301,974
    HMC1.2V560G/D816V11/17Human mast cell leukemia12511,3551506>25,000

Supplementary Materials

  • www.sciencetranslationalmedicine.org/cgi/content/full/9/414/eaao1690/DC1

    Fig. S1. Analysis of compound binding reveals broad type I activity across various forms of KIT.

    Fig. S2. BLU-285 inhibits KIT signaling in a KIT exon 11/17 human cell line.

    Fig. S3. BLU-285 exhibits differential activity on PDGFRA WT and V561D and D842V mutants.

    Fig. S4. Pharmacodynamic analysis of KIT signaling in a P815 allograft model of SM demonstrates in vivo target engagement.

    Fig. S5. BLU-285 is well tolerated in a KIT mutant exon 11/17 PDX model of relapsed GIST.

    Fig. S6. Histology of GIST PDX KIT mutant exon 11/17 tumors confirms tumor regression.

    Fig. S7. Histology of GIST PDX KIT mutant exon 11 tumors was correlated with tumor size regression.

    Fig. S8. BLU-285 is well tolerated in a KIT mutant exon 11 PDX model of primary GIST.

    Table S1. Human kinases with more than 90% binding by BLU-285, imatinib, sunitinib, regorafenib, crenolanib, and midostaurin are listed.

    Table S2. BLU-285 has selectivity for KIT D816V over several kinase antitargets.

    Table S3. Antitumor activity of BLU-285 and type II inhibitors across various KIT mutant–driven models of disease highlights robust activity of BLU-285.

  • Supplementary Material for:

    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 Miller, Beni Wolf, Nancy Kohl, Timothy Guzi, Nicholas Lydon, Andy Boral, Christoph Lengauer*

    *Corresponding author. Email: clengauer{at}blueprintmedicines.com

    Published 1 November 2017, Sci. Transl. Med. 9, eaao1690 (2017)
    DOI: 10.1126/scitranslmed.aao1690

    This PDF file includes:

    • Fig. S1. Analysis of compound binding reveals broad type I activity across various forms of KIT.
    • Fig. S2. BLU-285 inhibits KIT signaling in a KIT exon 11/17 human cell line.
    • Fig. S3. BLU-285 exhibits differential activity on PDGFRA WT and V561D and D842V mutants.
    • Fig. S4. Pharmacodynamic analysis of KIT signaling in a P815 allograft model of SM demonstrates in vivo target engagement.
    • Fig. S5. BLU-285 is well tolerated in a KIT mutant exon 11/17 PDX model of relapsed GIST.
    • Fig. S6. Histology of GIST PDX KIT mutant exon 11/17 tumors confirms tumor regression.
    • Fig. S7. Histology of GIST PDX KIT mutant exon 11 tumors was correlated with tumor size regression.
    • Fig. S8. BLU-285 is well tolerated in a KIT mutant exon 11 PDX model of primary GIST.
    • Table S1. Human kinases with more than 90% binding by BLU-285, imatinib, sunitinib, regorafenib, crenolanib, and midostaurin are listed.
    • Table S2. BLU-285 has selectivity for KIT D816V over several kinase antitargets.
    • Table S3. Antitumor activity of BLU-285 and type II inhibitors across various KIT mutant–driven models of disease highlights robust activity of BLU-285.

    [Download PDF]

Navigate This Article