Dasatinib (BMS-354825), a Dual SRC/ABL Kinase Inhibitor, Inhibits the Kinase Activity of Wild-Type, Juxtamembrane, and Activation Loop Mutant KIT Isoforms Associated with Human Malignancies

Abstract

Activating mutations of the activation loop of KIT are associated with certain human neoplasms, including the majority of patients with systemic mast cell disorders, as well as cases of seminoma, acute myelogenous leukemia (AML), and gastrointestinal stromal tumors (GISTs). The smallmolecule tyrosine kinase inhibitor imatinib mesylate is a potent inhibitor of wild-type (WT) KIT and certain mutant KIT isoforms and has become the standard of care for treating patients with metastatic GIST. However, KIT activation loop mutations involving codon D816 that are typically found in AML, systemic mastocytosis, and seminoma are insensitive to imatinib mesylate (IC 50 > 5-10 Mmol/L), and acquired KIT activation loop mutations can be associated with imatinib mesylate resistance in GIST. Dasatinib ( formerly BMS-354825) is a small-molecule, ATP-competitive inhibitor of SRC and ABL tyrosine kinases with potency in the low nanomolar range. Some small-molecule SRC/ABL inhibitors also have potency against WT KIT kinase. Therefore, we hypothesized that dasatinib might inhibit the kinase activity of both WT and mutant KIT isoforms. We report herein that dasatinib potently inhibits WT KIT and juxtamembrane domain mutant KIT autophosphorylation and KIT-dependent activation of downstream pathways important for cell viability and cell survival, such as Ras/mitogen-activated protein kinase, phosphoinositide 3-kinase/Akt, and Janus-activated kinase/signal transducers and activators of transcription. Furthermore, dasatinib is a potent inhibitor of imatinib-resistant KIT activation loop mutants and induces apoptosis in mast cell and leukemic cell lines expressing these mutations (potency against KIT D816Y J D816F > D816V). Our studies suggest that dasatinib may have clinical efficacy against human neoplasms that are associated with gain-of-function KIT mutations. (Cancer Res 2006; 66(1): 473-81)

Systemic mastocytosis in adults: 2015 update on diagnosis, risk stratification, and management

“…1) Dasatinib has shown efficacy in vitro against various KIT mutants including D816V [112,113]. Furthermore, dasatinib may synergize with PKC412 and chemotherapy in this regard [114][115][116].…”

Activate and resist: L576P-KIT in GIST

“…On the basis of this study, the structural similarity of both sunitinib and nilotinib with imatinib, and the analogous binding mode to KIT of these three small molecule ATP-competitive inhibitors (data are not shown), also account for the failure of their action on L576P mutated KIT. Therefore, relying on structural homology and other direct experimental (15) and modeling evidence, 6 we can hypothesize that dasatinib, for instance, could be an effective inhibitor of L576P KIT mutant in GISTs (in vitro experiments are ongoing).…”

Structure of an Unprecedented G-Quadruplex Scaffold in the Human c-kit Promoter

“…6,8 However, as with CML, resistance to Gleevec occurs as a result of deactivating mutations in the active site, which diminish binding and clinical effectiveness of the drug. 9 A number of new c-kit kinase inhibitors are currently being developed and evaluated with the aim of circumventing this resistance, 10 although they themselves may well produce new patterns of resistance mutations.…”