About Gastrointestinal Stromal Tumours (GIST), KIT and PDGFRA

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Structure and Function of Tyrosine Kinase Receptors: KIT and PDGFRA

KIT and PDGFRA belong to a highly homologous subfamily of tyrosine kinase receptors (TKRs). Both KIT and PDGFRA have similar functional domains: an extracellular ligand-binding domain, a transmembrane helix, and a cytoplasmic catalytic domain¹⁷. Despite their homology, most TKRs are encoded by distinct genes.

Click on the KIT – PDGFRA image to enlarge

Studies have revealed that GIST is a molecularly complex disease, with a varied mutational profile. Although most GISTs have mutations in exon 11 of KIT (66%), other mutations have been documented^16,18. Most gain-of-function mutations in KIT and PDGFRA occur in the juxtamembrane regions of the receptors. However, others, such as those in exons 13 and 17 (KIT)and exon 18 (PDGFRA), are in the cytoplasmic tyrosine kinase domain^18,19.

KIT and PDGFRA mutations are most commonly observed in GIST. Mutations that occur in several domains of these genes give rise to a variety of subtypes¹⁶. The ligands SCF (or steel factor) and PDGF bind to the TKRs KIT and PDGFRA, respectively. During normal cell growth, binding of these ligands to their respective receptors leads to phosphorylation in intracellular domains of the receptors. The resulting intracellular signalling leads to cell growth, changes in cell morphology, and prevention of apoptosis when new cells are needed^19,20.

Binding of the ligand SCF to the KIT TKR causes the receptor to dimerise, autophosphorylate, and become activated. Recruitment of other signalling proteins into a signalling complex then initiates a signal transduction cascade with some final steps occurring in the nucleus.

In GIST, constitutive activity of KIT and PDGFRA is associated with mutations in the genes that encode these TKRs. GISTs expressing activating mutations in either of these TKRs have a similar oncogenic phenotype. Constitutive TKR activation in the absence of ligand binding leads to abnormal, ligand-independent:

• Cell growth
• Changes in cell morphology
• Prevention of apoptosis^16,19,21,22

Adenosine triphosphate (ATP) molecules bind to mutated KIT and PDGFRA receptors and drive the continuous signalling for cell propagation. Glivec is designed to selectively bind to the mutant KIT and ATP-binding pocket. By binding to this active site, Glivec switches off downstream signalling, cells stop proliferating, and apoptosis ensues.

Other KIT-Expressing Tumours

KIT expression is not exclusive to GIST and has been documented by immunological criteria in a variety of other tumours. KIT is expressed in a number of other malignancies, such as angiosarcoma, Ewing sarcoma, pulmonary and other small-cell carcinomas, adenoid cystic and thymic carcinoma, and some ovarian and a few breast carcinomas²³. The role of KIT in the pathogenesis of these malignancies has not been defined.

Be prepared to recognise the Symptoms of GIST.

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