Clinical Resistance to STI-571 Cancer Therapy Caused by BCR-ABL Gene Mutation or Amplification

摘要: Clinical studies with the Abl tyrosine kinase inhibitor STI-571 in chronic myeloid leukemia demonstrate that many patients advanced stage disease respond initially but then relapse. Through biochemical and molecular analysis of clinical material, we find drug resistance is associated reactivation BCR-ABL signal transduction all cases examined. In six nine patients, was a single amino acid substitution threonine residue domain known to form critical hydrogen bond drug. This isoleucine sufficient confer reconstitution experiment. three progressive gene amplification. These provide evidence genetically complex cancers retain dependence on an initial oncogenic event suggest strategy for identifying inhibitors resistance.