Nintedanib Targets KIT D816V Neoplastic Cells Derived from Induced Pluripotent Stem cells of Systemic Mastocytosis.

  title={Nintedanib Targets KIT D816V Neoplastic Cells Derived from Induced Pluripotent Stem cells of Systemic Mastocytosis.},
  author={Marcelo A. S. Toledo and Malrun Gatz and Stephanie Sontag and Karoline V Gleixner and Gregor Eisenwort and Kristina Feldberg and Ahmed E. I. Hamouda and Frederick Kluge and Riccardo Guareschi and Giulia Rossetti and Antonio S. Sechi and Olli M. J. Dufva and Satu M. Mustjoki and Angela Maurer and Herdit Monika Sch{\"u}ler and Roman Goetzke and Till Braunschweig and Anne Kaiser and Jens Peter Panse and Mohamad Jawhar and Andreas Reiter and Frank C. Hilberg and Peter Ettmayer and Wolfgang Wagner and Steffen Koschmieder and Tim Henrik Br{\"u}mmendorf and Peter Valent and Nicolas Chatain and Martin Zenke},
The KIT D816V mutation is found in more than 80% of patients with systemic mastocytosis (SM) and is key to neoplastic mast cell (MC) expansion and accumulation in affected organs. KIT D816V therefore represents a prime therapeutic target for SM. Here we generated a panel of patient-specific KIT D816V induced pluripotent stem cells (iPSCs) from patients with aggressive SM (ASM) and mast cell leukemia (MCL) to develop a patient-specific SM disease model for mechanistic and drug discovery studies… 
CDK4/CDK6 Inhibitors Synergize with Midostaurin, Avapritinib, and Nintedanib in Inducing Growth Inhibition in KIT D816V+ Neoplastic Mast Cells
Together, CDK4/CDK6 inhibition is a potent approach to suppress the growth of neoplastic cells in AdvSM and induce apoptosis in CD34+/CD38− stem cells inAdvSM.
Comprehensive Analysis of Acquired Genetic Variants and Their Prognostic Impact in Systemic Mastocytosis
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The KIT and PDGFRA switch-control inhibitor DCC-2618 blocks growth and survival of multiple neoplastic cell types in advanced mastocytosis
DCC-2618 is a spectrum-selective pan KIT and PDGFRA inhibitor which blocks KIT D816V and multiple other kinase targets relevant to systemic mastocytosis and inhibits growth, survival and activation of multiple cell types relevant to advanced systemic mastocrytosis.
PKC412 inhibits in vitro growth of neoplastic human mast cells expressing the D816V-mutated variant of KIT: comparison with AMN107, imatinib, and cladribine (2CdA) and evaluation of cooperative drug effects.
It is shown that the novel TK-targeting drugs PKC412 and AMN107 counteract TK activity of D8 16V KIT and inhibit the growth of Ba/F3 cells with doxycycline-inducible expression of KIT D816V as well as the growthof primary neoplastic mast cells and HMC-1 cells harboring this KIT mutation.
Preclinical human models and emerging therapeutics for advanced systemic mastocytosis
The ROSAKIT D816V subclone has been successfully used to generate a unique in vivo model of advanced mastocytosis by injection into immunocompromised mice, which may allow in vivo validation of data obtained in vitro with targeted drugs directed against mastocyTosis.
Unique Effects of KIT D816V in BaF3 Cells: Induction of Cluster Formation, Histamine Synthesis, and Early Mast Cell Differentiation Antigens1
The D816V-mutated variant of KIT, a TK detectable in most patients with systemic mastocytosis, induces cluster formation and expression of several mast cell differentiation and adhesion Ags, including microphthalmia transcription factor, IL-4 receptor, histamine, CD63, and ICAM-1 in IL-3-dependent BaF3 cells.
A new human mast cell line expressing a functional IgE receptor converts to tumorigenic growth by KIT D816V transfection.
The data show that KIT D816V is a disease-propagating oncoprotein, but it does not activate MCs to release proinflammatory mediators, which may explain why mediator-related symptoms in SM occur preferentially in the context of a coexisting allergy.
Dasatinib (BMS-354825) inhibits KITD816V, an imatinib-resistant activating mutation that triggers neoplastic growth in most patients with systemic mastocytosis.
Significantly, dasatinib selectively kills primary neoplastic bone marrow mast cells from patients with systemic mastocytosis while sparing other hematopoietic cells and may be of clinical utility in other disease settings driven by activating KIT mutations.
The spleen microenvironment influences disease transformation in a mouse model of KITD816V-dependent myeloproliferative neoplasm
It is found that KITD816V mutant animals acquired a myeloproliferative neoplasm similar to polycythemia vera, marked by a massive increase in red blood cells and severe splenomegaly caused by excessive extramedullary erythropoiesis.
Molecular profiling of myeloid progenitor cells in multi-mutated advanced systemic mastocytosis identifies KIT D816V as a distinct and late event
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Impaired hematopoietic differentiation of RUNX1-mutated induced pluripotent stem cells derived from FPD/AML patients
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