Tyrosine kinase inhibitors in the treatment of systemic mastocytosis

Üstün, Celalettin; DeRemer, David L.; Akin, Cem

doi:10.1016/j.leukres.2011.05.006

Cited by 113 publications

(94 citation statements)

References 138 publications

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“…A novel promising strategy is to use KIT-targeting tyrosine kinase inhibitors (TKI) (19)(20)(21)(22)(23)(24)(25). However, the KIT D816V mutant is resistant against several of these TKI, including imatinib (21,25,26). PKC412 (midostaurin) is a multi-kinase inhibitor directed against wild type (wt) KIT and several KIT mutants, including D816V (21,27,28).…”

Section: Introductionmentioning

confidence: 99%

Target interaction profiling of midostaurin and its metabolites in neoplastic mast cells predicts distinct effects on activation and growth

et al. 2015

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Proteomic-based drug testing is an emerging approach to establish the clinical value and antineoplastic potential of multi-kinase inhibitors. The multikinase inhibitor midostaurin (PKC412) is a promising new agent used to treat patients with advanced systemic mastocytosis (SM). We examined the target interaction-profiles and the mast cell (MC)-targeting effects of two pharmacologically relevant midostaurin metabolites, CGP52421 and CGP62221. All three compounds, midostaurin and the two metabolites, suppressed IgE-dependent histamine secretion in basophils and MC with reasonable IC 50 values. Midostaurin and CGP62221 also produced growth-inhibition and dephosphorylation of KIT in the MC leukemia cell line HMC-1.2, whereas the second metabolite, CGP52421, that accumulates in vivo, showed no substantial effects.Chemical proteomic profiling and drug-competition experiments revealed that midostaurin interacts with KIT and several additional kinase-targets. The key downstream-regulator FES was recognized by midostaurin and CGP62221, but not by CGP52421 in MC lysates, whereas the IgEreceptor-downstream target SYK was recognized by both metabolites. Together, our data show that the clinically relevant midostaurin metabolite CGP52421 inhibits IgE-dependent histamine release, but is a weak inhibitor of MC proliferation which may have clinical implications and may explain why mediator-related symptoms improve in SM patients even when disease progression occurs.

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Section: Introductionmentioning

confidence: 99%

Target interaction profiling of midostaurin and its metabolites in neoplastic mast cells predicts distinct effects on activation and growth

et al. 2015

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“…Currently, IFN-a (2) and cladribine (2CdA) constitute the treatments of choice for the first-line therapy in systemic mastocytosis, however, with inadequate degree and duration of response (3). Imatinib has been approved by the U.S. Food and Drug Administration (FDA) for adult systemic mastocytosis patients without the KIT D816V mutation (4). Other TKIs such as dasatinib (5), midostaurin (PKC412; ref.…”

Section: Introductionmentioning

confidence: 99%

Ponatinib Induces Apoptosis in Imatinib-Resistant Human Mast Cells by Dephosphorylating Mutant D816V KIT and Silencing β-Catenin Signaling

Jin

Ding

Pan

2014

Molecular Cancer Therapeutics

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Gain-of-function mutations of membrane receptor tyrosine kinase KIT, especially gatekeeper D816V point mutation in KIT, render kinase autoactivation, disease progression, and poor prognosis. D816V KIT is found in approximately 80% of the patients with systemic mastocytosis, and is resistant to the first and second generations of tyrosine kinase inhibitors (TKI). The purpose of this investigation was aimed at exploring whether ponatinib (AP24534), a novel effective TKI against T315I Bcr-Abl, was active against D816V KIT. We discovered that ponatinib abrogated the phosphorylation of KIT harboring either V560G (sensitive to imatinib) or D816V mutation (resistant to imatinib) and the downstream signaling transduction. Ponatinib inhibited the growth of D816V KIT-expressing cells in culture and nude mouse xenografted tumor. Ponatinib triggered apoptosis by inducing the release of cytochrome c and AIF, downregulation of Mcl-1. Furthermore, ponatinib abrogated the phosphorylation of b-catenin at the site Y654, suppressed the translocation of b-catenin, and inhibited the transcription and DNA binding of TCF and the expression of its targets (e.g., AXIN2, c-MYC, and CCND1). Moreover, ponatinib was highly active against xenografted D816V KIT tumors in nude mice and significantly prolonged the survival of mice with aggressive systemic mastocytosis or mast cell leukemia by impeding the expansion and infiltration of mast cells with imatinibresistant D814Y KIT. Our findings warrant a clinical trial of ponatinib in patients with systemic mastocytosis harboring D816V KIT. Mol Cancer Ther; 13(5); 1217-30. Ó2014 AACR.

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“…Cutaneous and systemic mastocytosis have both been associated with somatic mutations in the gene encoding Kit, a type iii receptor tyrosine kinase [14][15][16] . The D816V mutation, a gain-of-function point mutation resulting in substitution of valine for aspartic acid at codon 816 within exon 17, is present in more than 90% of adult patients with sm 15 .…”

Section: Discussionmentioning

confidence: 99%

Symptomatic Response to Imatinib Mesylate in Cutaneous Mastocytosis Associated with Chronic Myelomonocytic Leukemia

et al. 2013

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1 major and 1 minor, or 3 minor World Health Organization diagnostic criteria, which are listed in Table ii 4 . Although cutaneous and systemic involvement can occur together in adults, children rarely experience systemic manifestations and often have self-limiting disease [5][6][7] . The treatment of sm in adults remains a challenge, in part because of its chronicity and heterogeneity. CASE DESCRIPTIONA 67-year-old white woman presented with progressive and debilitating pruritus of 5 years' duration.Her symptoms had begun with intermittent pruritus of her arms, which then progressed to involve unexposed areas. The condition was unresponsive to treatment with histamine antagonists and ultraviolet B phototherapy. Two years later, she was noted to have peripheral blood monocytosis. Bone marrow (bm) examination demonstrated hypercellularity, dysplastic erythroid precursors and megakaryocytes, and increased monocyte precursors (Figure 1), but no increase in blasts. Blood and marrow findings were diagnostic of chronic myelomonocytic leukemia (cmml) 1. Mast cell numbers and morphology were normal.When the patient presented to our tertiary care centre, her pruritus had become constant and involved her entire body. She was unable to sleep unless medicated with sedatives. She was struggling to work and was having suicidal thoughts. Hot showers exacerbated her pruritus, but symptoms persisted even with avoidance of triggers. She noted a chronic truncal rash and erythematous patches on her arms. She denied flushing, wheezing, and diarrhea. Her medical history was otherwise unremarkable.Physical examination revealed a fine maculopapular rash with tan lesions over the patient's anterior trunk, concentrated near the umbilicus and under the breasts, and erythematous plaques on the left arm. She did not have dermatographia.White blood cell count was 6.8×10 3 /μL, with 19% monocytes and 1% eosinophils. Hemoglobin ABSTRACTMastocytosis is an uncommon disorder defined by increased and abnormal mast cells in one or more tissues. Cutaneous mastocytosis (cm) is limited to the skin, with varying degrees of rash, pruritus, and disfigurement. Systemic mastocytosis (sm) typically involves the bone marrow, sometimes in association with other bone marrow disorders, including chronic myelomonocytic leukemia (cmml). Mastocytosis has been associated with somatic mutations in the gene encoding the tyrosine kinase Kit, leading to identification of Kit as a therapeutic target. The Kit inhibitor imatinib mesylate is approved for aggressive sm. We present an unusual patient with disabling pruritus from telangiectasia macularis eruptiva perstans, a subtype of cm, and cmml, but with no evidence of systemic mast cell disease. She was treated with imatinib and experienced marked improvement in her pruritus. Concomitant cm and cmml have not previously been reported, and the present report is the first of successful imatinib therapy in an adult patient with cm.

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Tyrosine kinase inhibitors in the treatment of systemic mastocytosis

Cited by 113 publications

References 138 publications

Target interaction profiling of midostaurin and its metabolites in neoplastic mast cells predicts distinct effects on activation and growth

Target interaction profiling of midostaurin and its metabolites in neoplastic mast cells predicts distinct effects on activation and growth

Ponatinib Induces Apoptosis in Imatinib-Resistant Human Mast Cells by Dephosphorylating Mutant D816V KIT and Silencing β-Catenin Signaling

Symptomatic Response to Imatinib Mesylate in Cutaneous Mastocytosis Associated with Chronic Myelomonocytic Leukemia

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