Molecular basis for treatment of gastrointestinal stromal tumours

Abstract

Abstract Gastrointestinal stromal tumour (GIST) is a rare turnour of the gastrointestinal tract that arises from activating mutations in KIT or platelet-derived growth factor receptor α (PDGFRα). Imatinib, a molecularly targeted therapy that inhibits the kinase activity of KIT, PDGFRs, ABL, and BCR-ABL, has been shown to be highly efficacious in patients with advanced GIST Most patients with advanced GIST treated with imatinib achieve either a partial response or experience stable disease, and median survival is longer than 3 years in either case. There is a strong correlation between the type of KIT or PDGFRA mutation and the clinical response to imatinib in patients with advanced GIST. In a phase II trial, significantly higher partial response rates were achieved in patients with GISTs harbouring KIT exon 11 mutations than in patients with GISTs harbouring KIT exon 9 mutations or in patients with GISTs exhibiting no detectable KIT or PDGFRA mutations. Resistance to imatinib treatment is a clinical challenge in the management of patients with advanced GIST Many imatinib-resistant GISTs have an associated secondary kinase mutation of KIT or PDGFRA . Continuing research efforts are directed at optimising the use of imatinib in patients with advanced GIST as well as the development of novel treatment approaches to prevent and/or treat imatinib-resistant clones of GIST.