Molecular analysis for new kinase mutations in imatinib resistant gastrointestinal stromal tumor patients

Abstract

4155 Background: Gastrointestinal stromal tumors (GISTs) are characterized by expression of activated mutation of KIT or platelet-derived growth factor receptor alpha (PDGFRA). Imatinib had now been widespread used for treatment of unresectable or metastatic GISTs. However, most patients developed resistant to imatinib in a period of 1∼2 years. We have recently found the resistance to imatinib in GIST might be related to additional mutations in the kinase domain and we intend to identify the secondary mutation in imatinib resistant GISTs in Taiwanese patients. Patients and Methods: From April 2001 to November 2005, 20 advanced GIST patients were treated in Taipei MMH. Within 32 months, 10 patients with initial near-complete response to imatinib developed disease progression and resistant to imatinib. Nine harbored mutations in KIT exon 11, and one harbored mutation in KIT exon 9 before imatinib treatment. Five patients expired and the other (residual) five patients received excision or biopsy of progression lesions. Genomic DNA extracted from paraffin-embedded specimens from alive patients, were analyzed by sequencing for KIT (exon 9, 11, 13, 17) and PDGFRA (exon 10, 12 14, 18) gene mutation. Results: Molecular analysis revealed two patients harbored KIT exon 13 mutation Val654Ala substitution in their progression lesion. The other three patients harbored KIT exon 17 mutation Asn822Lys substitution. Conclusion: The novel missense mutation of KIT exon 17 N822K has never been reported before. The finding of an association between new mutation and disease progression is very impressive. The relationship between secondary mutation in these kinases and clinical response to imatinib will require further investigation. No significant financial relationships to disclose.