New insights in tailored treatment of gastrointestinal stromal tumours

Abstract

Gastrointestinal strornal tumours (GISTs) are mesenchymal neoplasms that arise in the wall of the gastrointestinal tract. GISTs represent a continuum trom incidentally discoverd srnall modules with a benign or extremely low malignant potential to large to large highly malignant sarcomas. Characteristically, virtually all GISTS (>95 percent) overexpress the receptor tyrosine kinase and proto-oncogene KIT, which is used as an immunophenotypical marker for the diagnosis ot GIST. Moreover, oncogenic mutations that eiffect KIT or, much less often, the closely related platelet-derived growth factor receptor a (PDGFRA), have been detected in 85-90 percent of GISTs. These mutations result in ligand-independent, constitutive activation of these receptors leading to activation of cellular signal transduction cascades involved in cellular proliferation and survival. KIT and PDGFRA mutations are mutually exclusive and play fundamentalrole in the development of GIST. The tyrosine kinase inhibitor imatinib blocks the activity of KIT and PDGFRA. It has become the standard first-line treatment of patients with unresectable or metastasized GIST. Imatinib therapy resillts in high objective response and disease stabilisation rates but none of the patients are cured with this compound. The same holds t rue for second-line treatment with sunitinib , a tyrosine kinase inhibitor of KIT, PDGFR but also vascular endothelial growth factor (VEGFR) and FMS-like tyrosine kinase 3 (FLT3), of which clinical benefit, i.e. response and disease stabilisation, has been described but which is effective just as imatinib for a limited periocl of time. Therefore, new therapeutic strategies need to be developed.