EXEL-0862, a novel tyrosine kinase inhibitor, induces apoptosis in vitro and ex vivo in human mast cells expressing the KIT D816V mutation

Jingxuan Pan,Alfonso QuintáS-Cardama,Hagop M Kantarjian,Cem Akin,Taghi Manshouri,Peter Lamb,Jorge E Cortes,Ayalew Tefferi,Francis J Giles,Srdan Verstovsek

doi:10.1182/blood-2006-04-013805

Abstract

AbstractGain-of-function mutations of the receptor tyrosine kinase KIT play a key role in the pathogenesis of systemic mastocytosis (SM), gastrointestinal stromal tumors (GISTs), and some cases of acute myeloid leukemia (AML). Whereas KIT juxtamembrane domain mutations seen in most patients with GIST are highly sensitive to imatinib, the kinase activation loop mutant D816V, frequently encountered in SM, hampers the binding ability of imatinib. We investigated the inhibitory activity of the novel tyrosine kinase inhibitor EXEL-0862 against 2 subclones of human mast cell line-1 (HMC-1)—HMC-1.1, harboring the juxtamembrane domain mutation V560G, and HMC-1.2, carrying V560G and the activation loop mutation D816V, found in more than 80% of patients with SM. EXEL-0862 inhibited the phosphorylation of KIT in a dose-dependent manner and decreased cell proliferation in both mast cell lines with higher activity against HMC-1.2 cells. The phosphorylation of KIT-dependent signal transducer and activator of transcription-3 (STAT3) and STAT5 was abrogated upon exposure to nanomolar concentrations of EXEL-0862. In addition, EXEL-0862 induced a time- and dose-dependent proapoptotic effect in both mast cell lines and caused a significant reduction in mast-cell content in bone marrow samples from patients with SM harboring D816V and from those without the D816V mutation. We conclude that EXEL-0862 is active against KIT activation loop mutants and is a promising candidate for the treatment of patients with SM and other KIT-driven malignancies harboring active site mutations.

Highlights

Introduction the juxtamembrane domain mutationV560G, and human mast cell line-1 (HMC-1).2, carrying V560G and the activation loop mutation D816V, found in more than 80% of patients with Systemic mastocytosis (SM)
EXEL-0862 is a novel kinase inhibitor optimized for activity against fibroblast growth factor receptors (FGFRs), vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptors (PDGFRs), and FLT3 (Table 1)
We examined the effect of EXEL-0862 on KIT phosphorylation in HMC-1.2 cells harboring the KIT loop activation mutant D816V, which confers resistance to imatinib

Summary

Introduction

Introduction the juxtamembrane domain mutationV560G, and HMC-1.2, carrying V560G and the activation loop mutation D816V, found in more than 80% of patients with SM. Current therapy for ASM and MCL includes interferon-␣ and cladribine, but their efficacy is limited and the prognosis for patients remains poor.[3] most patients with SM harbor the activating oncogenic mutation KIT D816V, which involves the substitution of an aspartic residue at codon 816 of the activation loop with a valine residue. This mutation promotes receptor autophosphorylation without the requirement of stem-cell factor (SCF) stimulation.[4,5,6,7]

Methods

Results

Conclusion