Nintedanib targets KIT D816V neoplastic cells derived from induced pluripotent stem cells of systemic mastocytosis

Toledo, Marcelo Augusto Szymanski de; Gatz, Matthias; Sontag, Stephanie; Gleixner, Karoline V.; Eisenwort, Gregor; Feldberg, Kristina; Hamouda, Ahmed E.I.; Kluge, Frederick; Guareschi, Riccardo; Rossetti, Giulia; Sechi, Antonio; Dufva, Olli; Mustjoki, Satu; Maurer, Angela; Schüler, H; Goetzke, Roman; Braunschweig, Till; Kaiser, Anne; Panse, Jens; Jawhar, Mohamad; Reiter, Andreas; Hilberg, Frank; Ettmayer, Peter; Wagner, Wolfgang; Koschmieder, Steffen; Brümmendorf, Tim H.; Valent, Peter; Chatain, Nicolas; Zenke, Martin

doi:10.1182/blood.2019004509

Cited by 22 publications

(34 citation statements)

References 52 publications

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“…The main causes of mastocytosis are hypermorphic mutations in the proto-oncogene KIT (also referred to as c-kit). Whereas the KIT D816V mutation is present in nearly all SM cases (>80%) and can be targeted for therapy [ 339 ], the mutation pattern in CM patients varies [ 340 ]. KIT encodes for the receptor tyrosine kinase c-kit (CD117), which is the receptor for the MC growth factor SCF [ 341 ].…”

Section: Mast Cell-driven Skin Diseasesmentioning

confidence: 99%

Mast Cells in the Skin: Defenders of Integrity or Offenders in Inflammation?

Voß

Kotrba

Gaffal

et al. 2021

IJMS

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Mast cells (MCs) are best-known as key effector cells of immediate-type allergic reactions that may even culminate in life-threatening anaphylactic shock syndromes. However, strategically positioned at the host–environment interfaces and equipped with a plethora of receptors, MCs also play an important role in the first-line defense against pathogens. Their main characteristic, the huge amount of preformed proinflammatory mediators embedded in secretory granules, allows for a rapid response and initiation of further immune effector cell recruitment. The same mechanism, however, may account for detrimental overshooting responses. MCs are not only detrimental in MC-driven diseases but also responsible for disease exacerbation in other inflammatory disorders. Focusing on the skin as the largest immune organ, we herein review both beneficial and detrimental functions of skin MCs, from skin barrier integrity via host defense mechanisms to MC-driven inflammatory skin disorders. Moreover, we emphasize the importance of IgE-independent pathways of MC activation and their role in sustained chronic skin inflammation and disease exacerbation.

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Section: Mast Cell-driven Skin Diseasesmentioning

confidence: 99%

Mast Cells in the Skin: Defenders of Integrity or Offenders in Inflammation?

Voß

Kotrba

Gaffal

et al. 2021

IJMS

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“…Patient-specific KIT D816V induced pluripotent stem cells (so-called iPSCs) from patients with ASM and MCL represent a patient-specific SM disease model for mechanistic and drug discovery studies. The angiokinase inhibitor nintedanib which targets VEGFR, PDGFR, and FGFR is approved for the treatment of non-small-cell lung cancer, idiopathic pulmonary fibrosis, and other lung diseases by the FDA and EMA was identified as a novel KIT D816V inhibitor using this model [ 81 ]. These results suggest nintedanib as a new drug candidate for targeted therapy in patients with advanced SM.…”

Section: Discussionmentioning

confidence: 99%

New Insights into the Pathogenesis of Systemic Mastocytosis

2021

IJMS

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Mastocytosis is a type of myeloid neoplasm characterized by the clonal, neoplastic proliferation of morphologically and immunophenotypically abnormal mast cells that infiltrate one or more organ systems. Systemic mastocytosis (SM) is a more aggressive variant of mastocytosis with extracutaneous involvement, which might be associated with multi-organ dysfunction or failure and shortened survival. Over 80% of patients with SM carry the KIT D816V mutation. However, the KIT D816V mutation serves as a weak oncogene and appears to be a late event in the pathogenesis of mastocytosis. The management of SM is highly individualized and was largely palliative for patients without a targeted form of therapy in past decades. Targeted therapy with midostaurin, a multiple kinase inhibitor that inhibits KIT, has demonstrated efficacy in patients with advanced SM. This led to the recent approval of midostaurin by the United States Food and Drug Administration and European Medicines Agency. However, the overall survival of patients treated with midostaurin remains unsatisfactory. The identification of genetic and epigenetic alterations and understanding their interactions and the molecular mechanisms involved in mastocytosis is necessary to develop rationally targeted therapeutic strategies. This review briefly summarizes recent developments in the understanding of SM pathogenesis and potential treatment strategies for patients with SM.

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“…Using these iPSCs, the authors identified nintedanib, a US Food and Drug Administration-approved angiokinase inhibitor, as a potential new therapy for SM. 1…”

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confidence: 99%

“…ASM and MCL subgroups have poor outcomes with a median survival for MCL being ,1 year. [1][2][3] Therefore, there is an unmet need for novel therapies for these patients. Although the KIT D816V mutation is found in .80% of patients with SM, it does not appear that the KIT D816V mutation alone is sufficient to induce malignant transformation of mast cells.…”

mentioning

confidence: 99%

“…Induced fit molecular docking studies confirmed preferential targeting of nintedanib for KIT D816V compared with wild-type KIT, thus possibly eliminating some of the negative offtarget drug effects associated with TKIs. 1 Using patient-derived SM iPSCs, Toledo et al have eliminated critical barriers that prevented large-scale drug screens in a rare subset of hematologic malignancy and identified a potential new treatment of patients with SM with a poor prognosis. This study also demonstrates that the use of patient-specific iPSCs is a valuable tool to investigate other hematologic diseases where primary samples are limited to identify novel targets for therapy.…”

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confidence: 99%

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“Mast”ering drug discovery with iPSCs

Dorrance

2021

Blood

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In this issue of Blood, Toledo et al describe the generation of KIT D186Vinduced pluripotent stem cells (iPSCs) from patients with aggressive systemic mastocytosis (SM) to use as patient-specific models for mechanistic studies and drug discovery. Using these iPSCs, the authors identified nintedanib, a US Food and Drug Administration-approved angiokinase inhibitor, as a potential new therapy for SM. 1

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Nintedanib targets KIT D816V neoplastic cells derived from induced pluripotent stem cells of systemic mastocytosis

Cited by 22 publications

References 52 publications

Mast Cells in the Skin: Defenders of Integrity or Offenders in Inflammation?

Mast Cells in the Skin: Defenders of Integrity or Offenders in Inflammation?

New Insights into the Pathogenesis of Systemic Mastocytosis

“Mast”ering drug discovery with iPSCs

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