Systemic Mastocytosis: Following the Tyrosine Kinase Inhibition Roadmap

Piris-Villaespesa, Miguel; Álvarez‐Twose, Iván

doi:10.3389/fphar.2020.00443

Cited by 19 publications

(22 citation statements)

References 45 publications

(61 reference statements)

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“…The response rates were similar across sub-types, including in 16 patients with mast cell leukemia (MCL) [ 121 ]. The selective KIT D816V inhibitor avapritinib was recently FDA-approved for the treatment of ASM in June 2021 based on the emerging results of the phase I EXPLORER trial and phase II PATHFINDER trial [ 122 , 123 ]. At an interim analysis of the phase II PATHFINDER trial, ORR was 75%, and there was no observed difference in response rates between previously treated and untreated patients, including those receiving prior midostaurin therapy [ 122 ].…”

Section: Management Of Mast Cell Disordersmentioning

confidence: 99%

Mastocytosis and Mast Cell Activation Disorders: Clearing the Air

Jackson

Pratt

Rupprecht

et al. 2021

IJMS

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Mast cells are derived from hematopoietic stem cell precursors and are essential to the genesis and manifestations of the allergic response. Activation of these cells by allergens leads to degranulation and elaboration of inflammatory mediators, responsible for regulating the acute dramatic inflammatory response seen. Mast cells have also been incriminated in such diverse disorders as malignancy, arthritis, coronary artery disease, and osteoporosis. There has been a recent explosion in our understanding of the mast cell and the associated clinical conditions that affect this cell type. Some mast cell disorders are associated with specific genetic mutations (such as the D816V gain-of-function mutation) with resultant clonal disease. Such disorders include cutaneous mastocytosis, systemic mastocytosis (SM), its variants (indolent/ISM, smoldering/SSM, aggressive systemic mastocytosis/ASM) and clonal (or monoclonal) mast cell activation disorders or syndromes (CMCAS/MMAS). Besides clonal mast cell activations disorders/CMCAS (also referred to as monoclonal mast cell activation syndromes/MMAS), mast cell activation can also occur secondary to allergic, inflammatory, or paraneoplastic disease. Some disorders are idiopathic as their molecular pathogenesis and evolution are unclear. A genetic disorder, referred to as hereditary alpha-tryptasemia (HαT) has also been described recently. This condition has been shown to be associated with increased severity of allergic and anaphylactic reactions and may interact variably with primary and secondary mast cell disease, resulting in complex combined disorders. The role of this review is to clarify the classification of mast cell disorders, point to molecular aspects of mast cell signaling, elucidate underlying genetic defects, and provide approaches to targeted therapies that may benefit such patients.

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Section: Management Of Mast Cell Disordersmentioning

confidence: 99%

Mastocytosis and Mast Cell Activation Disorders: Clearing the Air

Jackson

Pratt

Rupprecht

et al. 2021

IJMS

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“…Oncogenic KIT mutations often occur in malignancies such as GISTs and mastocytosis [ 3 , 7 ], and our previous studies suggested that KIT mutants mediated distinct signaling pathways in addition to the ligand-independent activation [ [20] , [21] , [22] ]. In order to know whether PTPRE attenuates the activation of KIT mutants similarly as wild-type KIT, we further studied the function of PTPRE on the activation of KIT mutation D816V which is the most often happened mutation in mastocytosis.…”

Section: Resultsmentioning

confidence: 99%

“…KIT is a receptor tyrosine kinase that plays an important role in hematopoiesis, gametogenesis and melanogensis, and oncogenic KIT mutations have been identified in GISTs, mastocytosis, acute myeloid leukemia, melanoma and others [ [1] , [2] , [3] , 7 , 23 , 24 ]. Signaling studies of wild-type KIT and KIT mutants have showed that KIT mutants have different signaling properties in addition to the ligand independent activation which was considered as the main cause of cell transformation.…”

Section: Discussionmentioning

confidence: 99%

“…Oncogenic mutations of KIT have been identified in malignancies such as mastocytosis, gastrointestinal stromal tumors (GISTs), and acute myeloid leukemia. Mastocytosis is characterized by excessive mast cell infiltration in tissues, gene sequencing showed that KIT mutations are dominant mutations in mastocytosis with the D816V mutation in exon 17 of KIT most commonly occuring [ [3] , [4] , [5] , [6] ]. Similar as mastocytosis, GISTs are dominated by KIT mutations as well although they harbor different types of KIT mutations.…”

Section: Introductionmentioning

confidence: 99%

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Protein tyrosine phosphatase receptor type E (PTPRE) regulates the activation of wild-type KIT and KIT mutants differently

Zhang

Jiang

et al. 2021

Biochemistry and Biophysics Reports

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Activation of receptor tyrosine kinases needs tight control by tyrosine phosphatases to keep their normal function. In this study, we investigated the regulation of activation of the type III receptor tyrosine kinase KIT by protein tyrosine phosphatase receptor type E (PTPRE). We found that PTPRE can associate with wild-type KIT and inhibit KIT activation in a dose-dependent manner, although the activation of wild-type KIT is dramatically inhibited even when PTPRE is expressed at low level. The D816V mutation of KIT is the most frequently found oncogenic mutation in mastocytosis, and we found that PTPRE can associate and inhibit the activation of KIT/D816V in a dose dependent manner, but the inhibition is much weaker compared with wild-type KIT. Similar to mastocytosis, KIT mutations are the main oncogenic mutations in gastrointestinal stromal tumors (GISTs) although GISTs carry different types of KIT mutations. We further studied the regulation of the activation of GISTs-type KIT mutants and other mastocytosis-type KIT mutants by PTPRE. Indeed, PTPRE can almost block the activation of GISTs-type KIT mutants, while the activation of mastocytosis-type KIT mutants is more resistant to the inhibition of PTPRE. Taken together, our results suggest that PTPRE can associate with KIT, and inhibit the activation of both wild-type KIT and GISTs-type KIT mutants, while the activation of mastocytosis-type KIT mutants is more resistant to PTPRE.

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“…9,10 Tyrosine kinase inhibitors (TKI) like Masitinib, Imatinib or Midostaurin have demonstrated clinical activity in systemic mastocytosis, by blocking MC activation/proliferation. 11,12 Thus, it is tempting to suggest that TKI with high safety profiles may be used in SpA to block joint inflammation as it has been reported in RA. 13,14 Overall, although fundamental studies are required to clarify the role of MCs in SpA, we can conclude that these innate immune cells are not simple inflammatory bystanders but rather drivers of pain and inflammation.…”

mentioning

confidence: 99%