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

Gastroenterology. 2004 Jul;127(1):294-9. doi: 10.1053/j.gastro.2004.02.021.


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) and gastrointestinal stromal tumors (GIST). Primary and acquired resistance to the drug can occur in both diseases. Molecular mechanisms have been reported in CML and GIST for primary resistance, whereas extensive studies on the mechanisms responsible for secondary resistance have been almost exclusively reported for CML.

Methods: In a patient with advanced GIST undergoing imatinib therapy, an isolated progressing peritoneal mass was excised, along with 2 still-responding lesions. Complementary DNA and genomic DNA were analyzed by sequencing for c-Kit gene mutations. KIT receptor expression and phosphorylation status were assessed by immunoprecipitation and Western blot. Transient-transfection experiments were performed with mutagenized KIT constructs, and their activation status was assessed.

Results: In addition to an exon 11 mutation, shared among all of the analyzed lesions, a novel point mutation in c-Kit exon 14 resulting in T670I substitution was found only in the progressing lesion, which harbored a phosphorylated receptor, as opposed to the finding of an inactive receptor in responding lesions. Functional analyses showed that KIT/T670I is insensitive to imatinib and that T670I mutation, introduced in a receptor responding to imatinib, subverted its sensitivity to the drug.

Conclusions: This new mutation was confined to the progressing lesion; the resulting amino acidic substitution, T670I, affecting the ATP/imatinib pocket of KIT, makes it insensitive to the drug. Interestingly, this substitution is a homologue to the T315I mutation already reported in CML, where it is responsible for acquired resistance to imatinib.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abdominal Neoplasms / drug therapy*
  • Abdominal Neoplasms / genetics
  • Abdominal Neoplasms / secondary
  • Abdominal Neoplasms / surgery
  • Aged
  • Antineoplastic Agents / therapeutic use*
  • Benzamides
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics*
  • Fatal Outcome
  • Humans
  • Imatinib Mesylate
  • Male
  • Mutation
  • Piperazines / therapeutic use*
  • Proto-Oncogene Proteins c-kit / genetics*
  • Pyrimidines / therapeutic use*
  • Remission Induction
  • Stomach Neoplasms / drug therapy*
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / pathology
  • Stomach Neoplasms / surgery
  • Stromal Cells / drug effects
  • Stromal Cells / pathology
  • Surgical Procedures, Operative / methods


  • Antineoplastic Agents
  • Benzamides
  • Piperazines
  • Pyrimidines
  • Imatinib Mesylate
  • Proto-Oncogene Proteins c-kit