A new mutation in the KIT ATP pocket causes acquired resistance to imatinib in a gastrointestinal stromal tumor patient.

摘要: Abstract Background & Aims: Imatinib, a tyrosine kinase inhibitor of BCR-ABL, KIT, and platelet-derived growth factor receptor, is used in patients with chronic myelogenous leukemia (CML) gastrointestinal stromal tumors (GIST). Primary acquired resistance to the drug can occur both diseases. Molecular mechanisms have been reported CML GIST for primary resistance, whereas extensive studies on responsible secondary almost exclusively CML. Methods: In patient advanced undergoing imatinib therapy, an isolated progressing peritoneal mass was excised, along 2 still-responding lesions. Complementary DNA genomic were analyzed by sequencing c-Kit gene mutations. KIT receptor expression phosphorylation status assessed immunoprecipitation Western blot. Transient-transfection experiments performed mutagenized constructs, their activation assessed. Results: addition exon 11 mutation, shared among all lesions, novel point mutation 14 resulting T670I substitution found only lesion, which harbored phosphorylated as opposed finding inactive responding Functional analyses showed that KIT/T670I insensitive introduced imatinib, subverted its sensitivity drug. Conclusions: This new confined lesion; amino acidic substitution, T670I, affecting ATP/imatinib pocket makes it Interestingly, this homologue T315I already CML, where imatinib.