KIT/Val654 Ala receptor detected in one imatinib-resistant GIST patient.

To the Editor: We read with interest the article entitled ‘‘A Missense Mutation in KIT Kinase Domain 1 Correlates with Imatinib Resistance in Gastrointestinal Stromal Tumors’’ by Chen et al. because we have recently found the same mutation in a one of our surgically treated gastrointestinal stromal tumor patients. This patient had a metastatic gastrointestinal stromal tumor carrying a KIT exon 11 mutation (V559A) and underwent surgery because of clinical and radiological disease progression after imatinib treatment. Molecular analyses revealed an exon 11– activatingmutation in all but one of the tumoral metastatic nodules analyzed, whose features were consistent with active proliferation and carried the adjunctive exon 13 mutation (T1982C) responsible for ValAla substitution. Biochemical analyses revealed a KIT receptor that was equally phosphorylated and expressed in all the specimens regardless of the genotype. The karyotype was normal in all nodules, in line with the findings of Chen et al. However, we would like to comment on the unusually high frequency of the T1982C mutation in their case material (5 of 12 patients), which is strikingly different from the considerably lower percentage of point mutations in gastrointestinal stromal tumors with acquired resistance to imatinib observed by us. Among eight gastrointestinal stromal tumor patients progressing after imatinib treatment characterized bymolecular/biochemical and cytogenetic analyses, we identified only two point mutations in two different patients, one responsible for T670I substitution (1) and the other identical to that detected by Chen et al. Although their finding of an association between the mutation (with a normal karyotype) and disease progression under drug treatment is impressive, functional experiments attesting actual KIT/ ValAla imatinib resistance and its possible kinase-activating effect are strongly recommended to support this assumption. It is only with transfected cells expressing the double KITmutant (carrying exons 11 and 13 mutations on the same allele) and treated with different drug doses can provide useful information concerning the critical imatinib dose (if any) needed to deactivate/dephosphorylate the mutated receptor. As all their patients were treated with imatinib 400 mg/d, it is not known whether increasing the dose to 800 mg/d may prevent the development of resistant clones. We transfected COS1 cells with KIT/559/T670I and showed that this receptor is resistant to imatinib 15 mol/L, a clinically unachievable concentration. To acquire further insights into imatinib resistance and test new inhibitory molecules, suitable problem-oriented in vitro experiments coupled with molecular modeling are required.