Pharmacological targeting of the KIT growth factor receptor: a therapeutic consideration for mast cell disorders.
KIT is a member of the tyrosine kinase family of growth factor receptors which is expressed on a variety of haematopoietic cells including mast cells. Stem cell factor (SCF)-dependent activation of KIT is critical for mast cell homeostasis and function. However, when KIT is inappropriately activated, accumulation of mast cells in tissues results in mastocytosis. Such dysregulated KIT activation is a manifestation of specific activating point mutations within KIT, with the human D816V mutation considered as a hallmark of human systemic mastocytosis. A number of other activating mutations in KIT have recently been identified and these mutations may also contribute to aberrant mast cell growth. In addition to its role in mast cell growth, differentiation and survival, localized concentration gradients of SCF may control the targeting of mast cells to specific tissues and, once resident within these tissues, mast cell activation by antigen may also be amplified by SCF. Thus, KIT inhibitors may have potential application in multiple conditions linked to mast cells including systemic mastocytosis, anaphylaxis, and asthma. In this review, we discuss the role of KIT in the context of mast cells in these disease states and how recent advances in the development of inhibitors of KIT activity and function may offer novel therapies for the treatment of these disorders.
Jensen
B M
BM
RefLab, National University Hospital, Copenhagen N, Denmark.
Akin
C
C
Gilfillan
A M
AM
D000707:Anaphylaxis / Q000188:drug therapy / Q000503:physiopathology; D000818:Animals; D001249:Asthma / Q000188:drug therapy / Q000503:physiopathology; D016503:Drug Delivery Systems; D006801:Humans; D008415:Mastocytosis / Q000188:drug therapy* / Q000503:physiopathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D019009:Proto-Oncogene Proteins c-kit / Q000187:drug effects* / Q000378:metabolism; D019089:Stem Cell Factor / Q000378:metabolism
D047428:Protein Kinase Inhibitors; D019089:Stem Cell Factor; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit