A novel form of mastocytosis associated with a transmembrane c-kit mutation and response to imatinib

Akin, Cem; Fumo, Gerard; Yavuz, Akif Selim; Lipsky, Peter E.; Neckers, Len; Metcalfe, Dean D.

doi:10.1182/blood-2003-11-3816

Cited by 329 publications

(286 citation statements)

References 16 publications

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Section: Dasatinib As An Inhibitor Of Kit and Mastocytosis 287supporting

confidence: 71%

“…Previous studies showed an excellent correlation of the results of mast-cell viability in this assay with inhibition of KIT kinase activity, which was also associated with clinical response in one report. 5,24 Using this assay system, clear preferential cytotoxicity to neoplastic mast cells was demonstrated in bone marrow mononuclear-cell cultures established from patients with mastocytosis in the presence of dasatinib at 0.1 M concentration, with increased activity observed at 1 M. In contrast, imatinib had no significant activity at 1 M, as expected ( Figure 3B).To understand how dasatinib may be capable of binding to KIT even in the presence of the D816V mutation, we compared the crystal structure of imatinib bound to KIT with a model of dasatinib bound to the KIT kinase domain (Figure 4). D816 resides within the activation loop of KIT and is important for maintaining the inactive conformation that imatinib prefers by forming a hydrogen bond with N819.…”

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confidence: 99%

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Dasatinib (BMS-354825) inhibits KITD816V, an imatinib-resistant activating mutation that triggers neoplastic growth in most patients with systemic mastocytosis

Shah

Lee

Luo

et al. 2006

Blood

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Mastocytosis is associated with an activating mutation in the KIT oncoprotein (KIT D816V ) that results in autophosphorylation of the KIT receptor in a ligandindependent manner. This mutation is inherently resistant to imatinib and, to date, there remains no effective curative therapy for systemic mastocytosis associated with KIT D816V . Dasatinib (BMS-354825) is a novel orally bioavailable SRC/ ABL inhibitor that has activity against multiple imatinib-resistant BCR-ABL isoforms in vitro that is presently showing considerable promise in early-phase clinical trials of chronic myeloid leukemia (CML). Pharmacokinetic analysis suggests that high nanomolar concentrations of dasatinib can be achieved safely in humans. In this study, we demonstrate significant inhibitory activity of dasatinib against both wild-type KIT and the KIT D816V mutation in the nanomolar range in in vitro and cell-based kinase assays. Additionally, dasatinib leads to growth inhibition of a KIT D816V -harboring human mastocytosis cell line. Significantly, dasatinib selectively kills primary neoplastic bone marrow mast cells from patients with systemic mastocytosis while sparing other hematopoietic cells. Computer modeling suggests that the KIT D816V mutation destabilizes the inactive conformation of the KIT activation loop to which imatinib binds, but it is not predicted to impair binding of KIT IntroductionSystemic mastocytosis and mast-cell leukemia are relatively rare conditions that are characterized by a pathologic accumulation of mast cells in various tissues. 1 Previous work has demonstrated the clonal nature of the disorder as evidenced by an activating point mutation in the KIT receptor tyrosine kinase. 2,3 This mutation, KIT D816V , occurs near the activation loop of the kinase and can be identified in more than 80% of systemic mastocytosis cases and thus represents an attractive target for this disorder, for which few effective therapeutic options exist. 1 Although a small molecule tyrosine kinase inhibitor of KIT, imatinib mesylate, has been available to patients recently, both preclinical and clinical studies have demonstrated convincingly that the KIT D816V mutation is inherently resistant to imatinib. [4][5][6] The crystal structure of the wild-type KIT kinase domain has been solved in an autoinhibited state, with the activation loop of the kinase in a closed conformation, 7 similar to the cocrystal structure of imatinib bound to the ABL kinase domain. 7,8 These structural studies suggest that substitution of valine for aspartic acid at position 816 in KIT may alter the conformation of the activation loop and thus prevent imatinib from efficiently binding to KIT D816V .Inhibition of KIT D816V has thus become the focus of recent studies aiming to find a curative therapy for mast-cell disease, and several potential drug candidates with an ability to inhibit KIT D816V have been identified. [9][10][11][12][13][14][15] Dasatinib (BMS-354825) is a novel, potent, oral, multitargeted kinase inhibitor that targets ABL, SRC, KIT, PDGFR, ...

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Section: Dasatinib As An Inhibitor Of Kit and Mastocytosis 287supporting

confidence: 71%

mentioning

confidence: 99%

Dasatinib (BMS-354825) inhibits KITD816V, an imatinib-resistant activating mutation that triggers neoplastic growth in most patients with systemic mastocytosis

Shah

Lee

Luo

et al. 2006

Blood

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246

179

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“…Demonstrates in vitro efficacy against wild-type KIT and certain transmembrane (F522C) and juxta-membrane (V560G) KIT mutants, but not the common kinase (D816V) domain mutants [45,[105][106][107]. Similarly, not all juxta-membrane mutations may be sensitive to IM (e.g., V559I) [108].…”

Section: Imatinib Mesylate (Im)mentioning

confidence: 99%

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

Pardanani

2015

American J Hematol

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Disease overview: Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MC) in one or more extracutaneous organs.Diagnosis: The major criterion is presence of multifocal clusters of morphologically abnormal MC in the bone marrow. Minor diagnostic criteria include elevated serum tryptase level, abnormal MC expression of CD25 and/or CD2, and presence of KITD816V.Risk stratification: The 2008 World Health Organization classification of SM has been shown to be prognostically relevant. Classification of SM patients into indolent SM (ISM), aggressive SM (ASM), SM associated with a clonal non‐MC lineage disease (SM‐AHNMD), and mast cell leukemia (MCL) subgroups is a useful first step in establishing prognosis.Management: SM treatment is generally palliative. ISM patients have a normal life expectancy and receive symptom‐directed therapy; infrequently, cytoreductive therapy may be indicated for refractory symptoms. ASM patients have disease‐related organ dysfunction; interferon‐α (+/−corticosteroids) can control dermatological, hematological, gastrointestinal, skeletal, and mediator‐release symptoms, but is hampered by poor tolerability. Similarly, cladribine has broad therapeutic activity, with particular utility when rapid MC debulking is indicated; the main toxicity is myelosuppression. Imatinib has a therapeutic role in the presence of an imatinib‐sensitive KIT mutation or in KITD816‐unmutated patients. Treatment of SM‐AHNMD is governed primarily by the non‐MC neoplasm; hydroxyurea has modest utility in this setting; there is a role for allogeneic stem cell transplantation in select cases.Investigational Drugs: Recent data confirms midostaurin's significant anti‐MC activity in patients with advanced SM. Am. J. Hematol. 90:251–262, 2015. © 2015 Wiley Periodicals, Inc.

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“…More recently, an additional activating c-kit gene mutation has been detected at exon 10 encoding the transmembrane domain. 19) Imatinib mesylate (STI571; Gleevec; Novartis Pharma, Basel, Switzerland) is a selective inhibitor of certain tyrosine kinases including KIT, and has proven very effective in the treatment of patients with advanced GISTs, which are resistant to conventional chemotherapy, especially those harboring c-kit mutations at exon 11. 20) However, mutant KIT with Asp816Val at exon 17, which is the most common type of c-kit mutation in adult mastocytosis, is resistant to imatinib in vitro.…”

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confidence: 99%

c‐kit gene mutations in intracranial germinomas

et al. 2004

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Gain-of-function mutations of the c-kit gene and the expression of phosphorylated KIT are found in most gastrointestinal stromal tumors and mastocytosis. Further, almost all gonadal seminomas/ dysgerminomas exhibit KIT membranous staining, and several reports have clarified that some (10-25%) have a c-kit gene mutation. But, whether intracranial germinomas also have a c-kit gene mutation remains unsolved. To elucidate the presence, frequency, and location of c-kit gene mutations in intracranial germinomas, we analyzed five mutational hot spots (exons 9, 10, 11, 13, and 17) in the c-kit genomic DNA of 16 germinomas using polymerase chain reaction and direct sequencing. We found c-kit gene mutations at exon 11 (W557C) or 17 (D816V, D820V, and N822Y) in four germinomas (25.0%), although no statistically significant difference in any clinicopathological factor was found between patients with or without mutations. These results are similar to those seen in gonadal seminoma/dysgerminoma patients, and confirm that intracranial germinomas are exact counterparts of gonadal seminomas/dysgerminomas, as would be expected on histological and immunohistochemical grounds. Moreover, molecular targeting drugs such as imatinib mesylate (STI571), which is a selective inhibitor of KIT, might be promising agents for the treatment of intracranial germinomas with c-kit gene mutations. he c-kit proto-oncogene encodes a receptor tyrosine kinase (KIT) that is a member of the same subfamily as the receptors for platelet-derived growth factor and colony-stimulating factor-1. KIT consists of an extracellular domain with five immunoglobulin-like repeats, a transmembrane domain, a juxtamembrane domain, and tyrosine kinase (TK) I and II domains split by a kinase insert. The ligand for KIT is stem cell factor (SCF). The SCF-KIT system is critical for the normal development and survival of melanocytes, erythrocytes, germ cells, mast cells, and interstitial cells of Cajal (ICCs).1-3) On the other hand, gain-of-function mutations of the c-kit gene and the expression of phosphorylated KIT have been reported in tumors arising from these cell lineages, such as mast cell tumors, 4,5) gastrointestinal stromal tumors (GISTs), [6][7][8][9][10][11][12][13] which are thought to originate from ICCs in the gastrointestinal tract, and germ cell tumors (GCTs).14-18) Four mutational hot spots in different regions of the c-kit gene have been identified: in exons 9, 11, 13, and 17. More recently, an additional activating c-kit gene mutation has been detected at exon 10 encoding the transmembrane domain. 19) Imatinib mesylate (STI571; Gleevec; Novartis Pharma, Basel, Switzerland) is a selective inhibitor of certain tyrosine kinases including KIT, and has proven very effective in the treatment of patients with advanced GISTs, which are resistant to conventional chemotherapy, especially those harboring c-kit mutations at exon 11. 20) However, mutant KIT with Asp816Val at exon 17, which is the most common type of c-kit mutation in adult mastocytosis, is resistant to ...

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A novel form of mastocytosis associated with a transmembrane c-kit mutation and response to imatinib

Cited by 329 publications

References 16 publications

Dasatinib (BMS-354825) inhibits KITD816V, an imatinib-resistant activating mutation that triggers neoplastic growth in most patients with systemic mastocytosis

Dasatinib (BMS-354825) inhibits KITD816V, an imatinib-resistant activating mutation that triggers neoplastic growth in most patients with systemic mastocytosis

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

c‐kit gene mutations in intracranial germinomas

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