Acquired resistance to imatinib in gastrointestinal stromal tumours caused by multiple KIT mutations

Abstract

Gastrointestinal stromal tumours are characterised by the expression of the type III receptor tyrosine kinase v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT), and commonly carry activating mutations in the KIT gene, 1 Hirota S Isozaki K Moriyama Y et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998; 279: 577-580 Crossref PubMed Scopus (3790) Google Scholar or less often, in platelet-derived-growth-factor receptor alpha (PDGFRA). 2 Heinrich MC Corless CL Duensing A et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003; 299: 708-710 Crossref PubMed Scopus (1981) Google Scholar Imatinib, a multitargeted tyrosine-kinase inhibitor, has improved the treatment of advanced gastrointestinal stromal tumours, showing a clinical benefit in up to 80% of patients. 3 van Osteroom AT Judson I Verweij J et al. Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumors: a phase I study. Lancet. 2001; 358: 1421-1423 Summary Full Text Full Text PDF PubMed Scopus (1201) Google Scholar , 4 Heinrich MC Corless CL Demetri GD et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumors. J Clin Oncol. 2003; 21: 4342-4349 Crossref PubMed Scopus (1934) Google Scholar However, there is evidence for secondary resistance caused by the acquisition of new KIT mutations during treatment, leading to resistance against imatinib. 5 Wakai T Kanda T Hirota S et al. Late resistance to imatinib therapy in a metastatic gastrointestinal stromal tumour is associated with a second KIT mutation. Br J Cancer. 2004; 90: 2059-2061 Crossref PubMed Scopus (88) Google Scholar , 6 Tamborini E Bonadiman I Greco A et al. A new mutation in the KIT ATP pocket causes acquired resistance to imatinib in a gastrointestinal stromal tumour patient. Gastroenterology. 2004; 127: 294-299 Summary Full Text Full Text PDF PubMed Scopus (286) Google Scholar , 7 Demetri GD Desai J Fletcher J et al. SU11248, a multi-targeted tyrosine kinase inhibitor, can overcome imatinib (IM) resistance caused by diverse genomic mechanisms in patients (pts) with metastatic gastrointestinal stromal tumor (GIST). J Clin Oncol. 2004; 22 (abstr 3001): S14 Google Scholar We report findings from two patients with gastrointestinal stromal tumours with secondary resistance to imatinib.