Pharmacological targeting of the KIT growth factor receptor: a therapeutic consideration for mast cell disorders

Abstract

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.

Figure 1

Structure of human KIT and selected mutations associated with specific human disease states.

Figure 2

Binding of specific signalling proteins to phosphorylated tyrosine residues on KIT following receptor activation and the subsequent signalling events leading to mast cell responses. For clarity, only one receptor is shown in the figure. SCF-induced KIT dimerization enhances the tyrosine kinase activity associated with the split catalytic domain. This results in phosphorylation of specific tyrosine residues within the cytosolic domain of KIT. The tyrosine kinase, Lyn, may also contribute to this response. The consequential recruitment of critical signalling molecules such as the tyrosine kinases, Lyn and Fyn, the adaptor molecules, SHC and Grb2 and the signalling enzymes, PI3K and phospholipase Cγ, results in the activation of the Ras–Raf–mitogen-activated protein kinase (MAPK) pathway, the enhancement of intracellular calcium levels, and the activation of transcription factors leading to mast cell growth, differentiation and survival; enhanced cell migration and chemotaxis; and cytokine production. Activation of the JAK2 and STAT1/3/5 likely contributes to these responses. Concurrent with these events, KIT induces activation of the Tec kinase Btk and the adaptor molecule NTAL (non-T-cell activation linker), resulting in an enhancement of antigen-mediated degranulation and cytokine production. (For further details, please refer to Broudy, 1997; Linnekin, 1999; Tkaczyk et al., 2004; Iwaki et al., 2005; Lennartsson et al., 2005; Roskoski, 2005a, 2005b; Gilfillan and Tkaczyk, 2006; Reber et al., 2006.)