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	Vol	Issue	Date	Pages	Journal Short Title
Science translational medicine	9	414	2017 Nov 01		Sci Transl Med

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	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
KIT	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, Nov 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
KIT W557_K558del KIT Y823D	gastrointestinal stromal tumor	sensitive	Avapritinib	Preclinical - Pdx	Actionable	In a preclinical study, Ayvakit (avapritinib) 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 D816Y	mast cell neoplasm	predicted - sensitive	Avapritinib	Preclinical	Actionable	In a preclinical study, Ayvakit (avapritinib) 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
KIT exon17	Advanced Solid Tumor	sensitive	Avapritinib	Preclinical	Actionable	In a preclinical study, Ayvakit (avapritinib) 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 W557_K558del KIT V654A	gastrointestinal stromal tumor	sensitive	Avapritinib	Preclinical - Pdx	Actionable	In a preclinical study, Ayvakit (avapritinib) 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 V560G KIT D816V	mast-cell leukemia	sensitive	Avapritinib	Preclinical - Cell culture	Actionable	In a preclinical study, Ayvakit (avapritinib) inhibited Kit phosphorylation and proliferation of a mast cell leukemia cell line harboring KIT D816V and V560G in culture (PMID: 29093181).	29093181
KIT D820V	gastrointestinal stromal tumor	predicted - sensitive	Avapritinib	Case Reports/Case Series	Actionable	In a Phase I trial, Ayvakit (avapritinib) 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 W557_V559delinsF	gastrointestinal stromal tumor	sensitive	Avapritinib	Preclinical - Pdx	Actionable	In a preclinical study, Ayvakit (avapritinib) treatment resulted in tumor regression in patient-derived xenograft models of gastrointestinal stromal tumor harboring KIT W557_V559delinsF (PMID: 29093181).	29093181
KIT N822K	acute myeloid leukemia	sensitive	Avapritinib	Preclinical - Cell culture	Actionable	In a preclinical study, Ayvakit (avapritinib) inhibited Kit phosphorylation and proliferation of acute myeloid leukemia cells harboring KIT N822K in culture (PMID: 29093181).	29093181
KIT wild-type	acute megakaryocytic leukemia	decreased response	Avapritinib	Preclinical - Cell culture	Actionable	In a preclinical study, KIT wild-type megakaryocytic leukemia cells were less sensitive to Ayvakit (avapritinib) compared to cells harboring KIT mutations in culture (PMID: 29093181).	29093181
KIT V560G	mast-cell leukemia	sensitive	Avapritinib	Preclinical - Cell culture	Actionable	In a preclinical study, Ayvakit (avapritinib) inhibited Kit phosphorylation and proliferation of mast cell leukemia cells harboring KIT V560G in culture (PMID: 29093181).	29093181