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Data Point Out Why Certain Mutation in GI Tumor Occurs

-- Eric Metcalf

Friday, January 30, 2009

FRIDAY, Jan. 30 (HealthDay News) -- New evidence may explain why just isoleucine is naturally selected as a resistance mutant at position 670 of the tyrosine kinase KIT in patients with gastrointestinal stromal tumors (GIST) treated with imatinib, according to research published in the Feb. 4 issue of the Journal of the National Cancer Institute.

Tiziana Negri, Ph.D., of the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy, and colleagues used complementary DNA for an activated form of KIT to recreate point mutation-derived substitutions at the Thr670 codon. They then transfected constructs with these mutant receptors into COS1 African green monkey kidney cells, and assessed their activation according to the presence or absence of imatinib compared to the parental strain. They also incubated cells with each KIT mutant with imatinib to assess the ability of the drug to inhibit each variant.

The investigators found that Thr670Ile was the only mutant that maintained a high level of activity but was resistant to imatinib. Thr670Ala, Thr670Ser and Thr670Lys were inhibited by imatinib but showed only weak activity, and Thr670Pro and Thr670Arg showed no activity, the researchers report.

"In summary, these data explain why, among GIST patients who develop imatinib resistance, the mutation that causes the Thr670Ile substitution is the only mutation that is naturally selected at codon 670. Indeed, isoleucine is the only amino acid substitution that can arise through point mutation at that position that is able to yield a selective advantage to tumors under conditions of imatinib treatment," the authors conclude.

Full Text

Specialties Cardiology
Diabetes & Endocrinology
Internal Medicine
Family Practice

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