Reference Detail

Ref Type Journal Article
PMID (29093181)
Authors Evans EK, Gardino AK, Kim JL, Hodous BL, Shutes A, Davis A, Zhu XJ, Schmidt-Kittler O, Wilson D, Wilson K, DiPietro L, Zhang Y, Brooijmans N, LaBranche TP, Wozniak A, Gebreyohannes YK, Schöffski P, Heinrich MC, DeAngelo DJ, Miller S, Wolf B, Kohl N, Guzi T, Lydon N, Boral A, Lengauer C
Title A precision therapy against cancers driven by KIT/PDGFRA mutations.
Journal Science translational medicine
Vol 9
Issue 414
Date 2017 Nov 01
URL
Abstract Text 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
D816E missense unknown KIT D816E lies within the protein kinase domain of the Kit protein (UniProt.org). D816E has been identified in the scientific literature (PMID: 29100343, PMID: 29093181) but has not been biochemically characterized and therefore, its effect on Kit protein function is unknown (PubMed, Mar 2019).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KIT D816V KIT V560G mast-cell leukemia sensitive Avapritinib Preclinical - Cell culture Actionable In a preclinical study, BLU-285 inhibited Kit phosphorylation and proliferation of a mast cell leukemia cell line harboring KIT D816V and V560G in culture (PMID: 29093181). 29093181
PDGFRA D842V Advanced Solid Tumor sensitive Avapritinib Preclinical - Cell culture Actionable In a preclinical study, BLU-285 inhibited Kit phosphorylation in transformed cells overexpressing PDGFRA D842V in culture (PMID: 29093181). 29093181
KIT W557_V559delinsF gastrointestinal stromal tumor sensitive Avapritinib Preclinical - Pdx Actionable In a preclinical study, BLU-285 treatment resulted in tumor regression in patient-derived xenograft models of gastrointestinal stromal tumor harboring KIT W557_V559delinsF (PMID: 29093181). 29093181
PDGFRA D842V gastrointestinal stromal tumor sensitive Avapritinib Phase I Actionable In a Phase I trial, BLU-285 treatment resulted in partial response lasted for more than 15 cycles of treatment, and sustained reduction of plasma PDGFRA D842V in a patient with gastrointestinal stromal tumor harboring PDGFRA D842V, whose disease had progressed on previous Gleevec (imatinib mesylate), Sprycel (dasatinib), and Crenolanib treatment (PMID: 29093181; NCT02508532). 29093181
KIT wild-type megakaryocytic leukemia decreased response Avapritinib Preclinical - Cell culture Actionable In a preclinical study, KIT wild-type megakaryocytic leukemia cells were less sensitive to BLU-285 compared to cells harboring KIT mutations in culture (PMID: 29093181). 29093181
KIT N822K acute myeloid leukemia sensitive Avapritinib Preclinical - Cell culture Actionable In a preclinical study, BLU-285 inhibited Kit phosphorylation and proliferation of acute myeloid leukemia cells harboring KIT N822K in culture (PMID: 29093181). 29093181
KIT D820V gastrointestinal stromal tumor sensitive Avapritinib Phase I Actionable In a Phase I trial, BLU-285 treatment resulted in tumor reduction lasting through 15 cycles of treatment in a patient with gastrointestinal stromal tumor harboring KIT D820V, whose disease had progressed on previous Gleevec (imatinib), Sutent (sunitinib), and Stivarga (regorafenib) treatment (PMID: 29093181; NCT02508532). 29093181
KIT V560G mast-cell leukemia sensitive Avapritinib Preclinical - Cell culture Actionable In a preclinical study, BLU-285 inhibited Kit phosphorylation and proliferation of mast cell leukemia cells harboring KIT V560G in culture (PMID: 29093181). 29093181
Unknown unknown indolent systemic mastocytosis not applicable Avapritinib Phase I Actionable In a Phase I trial, BLU-285 treatment reduced bone marrow mast cell infiltration in a patient with systemic mastocytosis (PMID: 29093181; NCT02561988). 29093181
KIT W557_K558del KIT Y823D gastrointestinal stromal tumor sensitive Avapritinib Preclinical - Pdx Actionable In a preclinical study, BLU-285 inhibited Kit phosphorylation and resulted in tumor regression in patient-derived xenograft models of Gleevec (imatinib mesylate)-resistant gastrointestinal stromal tumor harboring KIT W557_K558del and Y823D (PMID: 29093181). 29093181
KIT W557_K558del KIT V654A gastrointestinal stromal tumor sensitive Avapritinib Preclinical - Pdx Actionable In a preclinical study, BLU-285 inhibited Kit phosphorylation and resulted in tumor regression in patient-derived xenograft models of Gleevec (imatinib)-resistant gastrointestinal stromal tumor harboring KIT W557_K558del and V654A (PMID: 29093181). 29093181
KIT exon 17 Advanced Solid Tumor sensitive Avapritinib Preclinical Actionable In a preclinical study, BLU-285 inhibited Kit phosphorylation and proliferation of various tumor cell lines harboring KIT exon 17 mutations in culture, and induced tumor regression in an allograft animal model (PMID: 29093181). 29093181
KIT D816Y mast cell neoplasm sensitive Avapritinib Preclinical Actionable In a preclinical study, BLU-285 inhibited Kit phosphorylation and proliferation of murine mastocytoma cells harboring KIT D814Y (corresponding to human D816Y) in culture, and resulted in tumor regression in allograft animal models (PMID: 29093181). 29093181
PDGFRA V561D Advanced Solid Tumor sensitive Avapritinib Preclinical - Cell culture Actionable In a preclinical study, BLU-285 inhibited Kit phosphorylation in transformed cells overexpressing PDGFRA V561D in culture (PMID: 29093181). 29093181