Secondary resistance to imatinib in patients with gastrointestinal stromal tumors through an acquired KIT exon 17 mutation

Molecular Medicine Reports
Chun-Meng WangY Q Shi

Abstract

Although imatinib has demonstrated a potent effect on advanced gastrointestinal stromal tumors (GISTs) and has improved the survival of GIST patients, with its prolonged use imatinib resistance is becoming an increasing clinical problem. Mechanisms of secondary resistance are still under investigation. Our study aimed to determine the mechanism of acquired resistance to imatinib in GISTs. Using bidirectional PCR DNA sequencing, we sequenced exons 9, 11, 13 and 17 of the KIT gene and exons 12 and 18 of the PDGFRA gene in secondary resistant lesions obtained from 18 GIST patients after treatment with imatinib. Fourteen of 18 cases carried activating mutations in the KIT gene, with a mutation encoding the juxtamembrane domain present in exon 11 in 12 cases, in exon 13 in 1 case, and in exon 9 in 1 case. In 4 of 10 imatinib-resistant patients, an identical novel missense mutation (T2467G) was found in exon 17, resulting in a substitution of tyrosine by aspartic acid at codon 823 (Y823D). In conclusion, the exon 17 missense mutation T2467G in the tyrosine kinase domain of the KIT gene is correlated with imatinib resistance.

Citations

May 25, 2011·Journal of Translational Medicine·Alessandra MaledduGuido Biasco
Oct 29, 2008·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Michael C HeinrichGeorge D Demetri

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