Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification

Clinical studies with the AN tyrosine kinase inhibitor STI-571 in chronic m yeloid leukemia demonstrate that many patients with advanced stage disease respond initially but then relapse. Through biochemical and molecular analy sis of clinical material, we find that drug resistance is associated with t he reactivation of BCR-ABL signal transduction in all cases examined. In si x of nine patients, resistance was associated with a single amino acid subs titution in a threonine residue of the AN kinase domain known to form a cri tical hydrogen bond with the drug. This substitution of threonine with isol eucine was sufficient to confer STI-571 resistance in a reconstitution expe riment. In three patients, resistance was associated with progressive BCR-A BL gene amplification. These studies provide evidence that genetically comp lex cancers retain dependence on an initial oncogenic event and suggest a s trategy for identifying inhibitors of STI-571 resistance.