Effects of AMN107, a novel aminopyrimidine tyrosine kinase inhibitor, on human mast cells bearing wild-type or mutated codon 816 c-kit
Introduction
Systemic mastocytosis (SM) is characterized by a clonal accumulation of mast cells (MC) in bone marrow and other tissues [1], [2]. Malignant MC are abnormally spindle-shaped, express aberrant surface markers (CD2 and CD25), and carry, in most cases, a mutation involving codon 816 of the c-kit gene (D816V) [1], [2]. This mutation results in constitutively activated c-kit receptor tyrosine kinase activity that is believed to be important for disease progression. Thus, agents that antagonize this mutated form of c-kit may have clinical benefit in SM [3]. MC lines with D816V mutation may serve as effective screening models to test for such agents. Imatinib mesylate (imatinib, Gleevec®), a highly effective inhibitor of the Bcr-Abl tyrosine kinase, is associated with high complete cytogenetic remission rates in patients with chronic myelogenous leukemia (CML) resistant or intolerant to imatinib [4]. Because of its potential activity on c-kit tyrosine kinase, imatinib was evaluated in vitro against MC expressing the D816V tyrosine kinase mutant but proved ineffective [5]. AMN107 is a novel, potent, orally bioavailable Bcr-Abl inhibitor, rationally designed based on the crystallographic structure of the imatinib–Bcr-Abl complex. Against CML cell lines, AMN107 exhibited 20- to 50-fold higher potency as a Bcr-Abl inhibitor than imatinib [6], [7]. We have recently reported on the activity of AMN107 in both imatinib-sensitive and -resistant p190 Bcr-Abl-expressing lymphoid cells and p210 Bcr-Abl-expressing myeloid leukemic cells [8], [9].
In the current study, we report on the preclinical activity of AMN107 against MC lines harboring juxtamembrane and activation loop mutations and compared it to that of imatinib. Moreover, we compared the activity of both tyrosine kinase inhibitors against primary MC from patients with SM harboring D816V c-kit. Our results suggest equipotency of both tyrosine kinase inhibitors against the above-mentioned cellular targets.
Section snippets
Drugs
Imatinib and AMN107 (NVP-AMN107-NX; 4-methyl-N-[3-(4-methyl-1H-imidazol)-5-(trifluoromethyl) phenyl]-3-(3-pyridinyl)-2pyridinyl]amino] benz amide) were kindly provided by Novartis Pharma AG, Basel, Switzerland. Drug 10 mM stock dilutions were prepared in dimethylsulfoxide and stored at −20 °C (imatinib) or +4 °C (AMN107). Working dilutions were prepared in 10% media just before use.
Cell lines
MC lines were kindly provided by Dr. Joseph Butterfield (Mayo Clinic, Rochester, MN): HMC-1560 carrying juxtamembrane
Results and discussion
SM is a rare hematological malignancy with variable clinical outcome [1], [2]. Most patients present with indolent SM and exhibit signs and symptoms related to MC activation. In these cases, empirical therapy aiming to improve quality of life, rather than cytoreductive therapy, is customarily employed [1], [2]. On the other hand, patients presenting with aggressive SM (ASM) experience organ dysfunction due to infiltration of neoplastic MC and their prognosis is dismal [1], [2]. Current
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2014, Journal of Allergy and Clinical ImmunologyCitation Excerpt :Patients with mastocytosis often carry a gain-of-function mutation of KIT (D816V), and most KIT inhibitors cannot sufficiently block the mutated KIT.110 Imatinib and nilotinib are 2 compounds with inhibitory effects on the KIT-mediated MC response, but they are not suitable for the treatment of patients with mastocytosis carrying mutated KIT (D816V).111,112 Imatinib has been reported to be efficient in the treatment of arthritis and mastocytosis,110,113-115 whereas nilotinib has recently been shown to have an antiallergic effect on MC-mediated anaphylaxis.116