Chemotherapy and dasatinib induce long-term hematologic and molecular remission in systemic mastocytosis with acute myeloid leukemia with KITD816V

Üstün, Celalettin; Corless, Christopher L.; Savage, Natasha M.; Fiskus, Warren; Manaloor, Elizabeth; Heinrich, Michael C.; Lewis, Grant; Ramalingam, Preetha; Kepten, Ilana; Jillella, Anand; Bhalla, Kapil N.

doi:10.1016/j.leukres.2008.09.027

Cited by 65 publications

(42 citation statements)

References 18 publications

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“…Bim, a proapoptotic Bcl-2 homology 3-only protein (36), is elevated after ablation of Bcr-Abl and epidermal growth factor receptor signaling (37)(38)(39). However, our data showed that the levels of Bim were unperturbed after HHT treatment (Figs.…”

Section: Hht Induces Apoptosis In D816v Kit-expressing Cells and Decrmentioning

confidence: 55%

The Antitumor Activity of Homoharringtonine against Human Mast Cells Harboring the KIT D816V Mutation

Jin

Lu²,

Cao³

et al. 2010

Molecular Cancer Therapeutics

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Gain-of-function mutations of the receptor tyrosine kinase KIT play a critical role in the pathogenesis of systemic mastocytosis (SM) and gastrointestinal stromal tumors. The various juxtamembrane type of KIT mutations, including V560G, are found in 60% to 70% of patients with gastrointestinal stromal tumors; loop mutant D816V, which exists in ∼80% of SM patients, is completely resistant to imatinib. In the present study, we hypothesized that homoharringtonine (HHT), a protein synthesis inhibitor, would decrease the level of KIT protein by inhibiting translation, resulting in a decreased level of phospho-KIT and abrogating its constitutive downstream signaling. Imatinib-sensitive HMC-1.1 cells harboring the mutation V560G in the juxtamembrane domain of KIT, imatinib-resistant HMC-1.2 cells harboring both V560G and D816V mutations, and murine P815 cells were treated with HHT and analyzed in terms of growth, apoptosis, and signal transduction. The in vivo antitumor activity was evaluated by using the murine mast cell leukemia model. Our results indicated that HHT effectively inhibited the growth and induced apoptosis in cells bearing both V560G and D816V or D814Y KIT. Additionally, HHT inhibited the KIT-dependent phosphorylation of downstream signaling molecules Akt, signal transducer and activator of transcription 3 and 5, and extracellular signal-regulated kinase 1/2. Furthermore, HHT significantly prolonged the survival duration of mice with aggressive SM or mast cell leukemia by inhibiting the expansion and infiltration of imatinib-resistant mast tumor cells harboring imatinib-resistant D814Y KIT. Collectively, we show that HHT circumvents D816V KITelicited imatinib resistance. Our findings warrant a clinical trial of HHT in patients with SM harboring D816V or D814Y KIT. Mol Cancer Ther; 9(1); 211-23. ©2010 AACR.

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Section: Hht Induces Apoptosis In D816v Kit-expressing Cells and Decrmentioning

confidence: 55%

The Antitumor Activity of Homoharringtonine against Human Mast Cells Harboring the KIT D816V Mutation

Jin

Lu²,

Cao³

et al. 2010

Molecular Cancer Therapeutics

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“…Furthermore, dasatinib may synergize with PKC412 and chemotherapy in this regard [114][115][116]. In the largest study of dasatinib therapy in SM [117], the drug was given at a starting dose of 70 mg PO bid to 33 SM patients:18 ISM, 9 ASM, and 6 with SM-AHNMD.…”

Section: Investigational Agentsmentioning

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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“…6), semaxinib (7), and EXEL-0862 (8) have been reported to exhibit growth inhibitory and apoptosis induction effects in mast cells harboring D816V KIT mutation. Although Ustun and colleagues reported that dasatinib has efficacy in systemic mastocytosis-AML patients bearing D816V KIT, a phase II study from an independent group did not support the potency of dasatinib against D816V KIT (9). Although midostaurin (PKC412) has a synergistic effect with dasatinib to inhibit the growth of neoplastic mast cells (6,10), the long-term benefit of PKC412 has not yet been determined.…”

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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Chemotherapy and dasatinib induce long-term hematologic and molecular remission in systemic mastocytosis with acute myeloid leukemia with KITD816V

Cited by 65 publications

References 18 publications

The Antitumor Activity of Homoharringtonine against Human Mast Cells Harboring the KIT D816V Mutation

The Antitumor Activity of Homoharringtonine against Human Mast Cells Harboring the KIT D816V Mutation

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

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

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