Understanding GIST
Pathophysiology
Cancers grow as a consequence of the disruption of the normal balance between the rate of cell-cycle progression (cell division) and cell growth (cell mass), and the rate of apoptosis (programmed cell death).1 Aberrant cellular signal transduction is a driving force on both sides of the equation as well as in the process of malignant transformation.2
Receptor tyrosine kinases are among the most critical groups of signaling molecules involved in cellular regulation.2-5 KIT and PDGFRα proteins are type III receptor tyrosine kinases,6 structurally homologous with platelet-derived growth factor receptor beta (PDGFRβ), colony-stimulating factor-1 receptor, and the FMS-related receptor FLT3. Members of this family contain an intracellular kinase domain and 5 extracellular immunoglobulin-like domains separated by a kinase insert (Figure 1).3,7-9 KIT and PDGFRα are the primary molecular cause of GIST tumorigenesis.10-12
The activity of receptor tyrosine kinases is normally tightly regulated. When receptor tyrosine kinase signaling is perturbed by mutations and other genetic alterations, dysregulated kinase activity and malignant transformation result.2
Figure 1
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KIT receptor kinase structure and function. Activation by mutation or ligand leads to transphosphorylation, binding of adenosine triphosphate (ATP), and phosphorylation of downstream substrates. These downstream molecules drive the transcription of genes involved in supporting the tumor phenotype. Binding of Glivec interrupts the signaling pathway. Adapted with permission from d’Amato G et al. Cancer Control. 2005;12:44-56.3
KIT
KIT is the product of the KIT proto-oncogene.7,9 KIT is expressed on hematopoietic stem cells, melanocytes, mast cells, germ cells, and ICCs.9,13
Native KIT is expressed as a transmembrane protein. Normal KIT activation occurs when the receptor is bound by stem-cell factor, its cognate ligand, also referred to as mast-cell growth factor or steel factor.9,14,15 When KIT binds to stem-cell factor, 2 KIT proteins interact (Figure 2).14,2 This process, known as homodimerization, activates the cytoplasmic tyrosine kinase domains, resulting in autophosphorylation of selected tyrosine residues. Substrates and adapter proteins bind to phosphorylated tyrosine residues and in some cases are directly phosphorylated by KIT. This process activates cell-signaling cascades that regulate cell behaviour (Figure 3).14
Critical downstream signaling mechanisms include activation of cell-survival (antiapoptotic) proteins and cell-proliferation–related proteins.3,9,14 Glivec® competitively binds to the adenosine triphosphate (ATP)–binding pocket of KIT and PDGFR to prevent phosphorylation, interrupting proliferative and antiapoptotic intracellular signaling pathways.16,17
Figure 2
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Ligand-induced activation of KIT tyrosine kinase activity. (A) Native KIT is expressed as a transmembrane protein. The cytoplasmic domain contains the tyrosine kinase portion of the protein (split into 2 domains, TK1 and TK2, as indicated). An arrow indicates the location of the juxtamembrane domain (JM). (B) Binding of dimeric ligand stem-cell factor (SCF) results in physical interaction of 2 KIT proteins. (C) Ligand-induced dimerization activates the cytoplasmic tyrosine kinase domains, resulting in autophosphorylation (P) of selected tyrosine residues. (D) Substrates and adapter proteins bind to phosphorylated tyrosine residues and in some cases are directly phosphorylated by KIT. Adapted with permission from Heinrich MC et al. Hum Pathol. 2002;33:484-495.14
Figure 3
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Intracellular signal transduction pathways activated by KIT receptor tyrosine kinase activation. Adapted with permission from Heinrich MC et al. Hum Pathol. 2002;33:484-495.14
Constitutive activation of the KIT receptor tyrosine kinase
Constitutive activation of the KIT receptor tyrosine kinase, overcoming normal controls, is a pivotal pathogenic event in most GISTs. Point mutations involving either cytoplasmic or extracellular domains of the receptor allow structural changes favoring receptor oligomerization and cross-phosphorylation in the absence of ligand binding (Figure 4).14 Regulatory-type KIT mutations occur in most GISTs. The intracellular juxtamembrane region, encoded by exon 11, is the best-characterized regulatory region of KIT (Figure 5).14 An alpha helix in this region suppresses KIT phosphorylation and kinase activity. Mutations that disrupt the alpha helix constitutively activate KIT.
Figure 4
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Oncogenic mutations of the KIT juxtamembrane (JM) domain result in ligand-independent KIT dimerization and activation of the kinase enzymatic domain. KIT activation is followed by receptor autophosphorylation and binding of substrate and adapter proteins. In some cases KIT directly phosphorylates these KIT-associated proteins. Adapted with permission from Heinrich MC et al. Hum Pathol. 2002;33:484-495.14
Figure 5
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Oncogenic KIT mutations affect the extracellular, juxtamembrane (JM), and kinase (TK1 and TK2) domains. Adapted with permission from Heinrich MC et al. Hum Pathol. 2002;33:484-495.14
PDGFRA
Although most GISTs have activating KIT mutations, a subset express wild-type KIT. An investigation of alternative receptor tyrosine kinase oncoproteins with a role in GIST pathogenesis found that approximately 35% (14 of 40) of GISTs without KIT mutations expressed intragenic activation mutations in PDGFRA18 and that KIT and PDGFRA mutations are alternative, mutually exclusive oncogenic mutations in GIST.
Like KIT, PDGFRα normally functions in the regulation of cell proliferation.13 PDGFRs are expressed on myeloid and erythroid precursors in bone marrow, as well as on monocytes, fibroblasts, megakaryocytes, endothelial cells, glial cells, and osteoblasts.
The binding of cognate ligands to PDGFRα and PDGFRβ induces dimerization of receptor polypeptides, activating receptor kinase activity (Figure 6).13,19,20 In the malignant process, constitutive activation of mutant PDGFRs results from point mutations or chromosomal translocations.13,21
Figure 6
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Structure of KIT and PDGFRα. Exons from genes encoding specific regions of KIT or PDGFRα are indicated in relation to the structural features of the proteins. TK, tyrosine kinase. Adapted with permission from Heinrich MC et al. J Clin Oncol. 2002;20:1692-1703.20
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