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

ME Gorre, M Mohammed, K Ellwood, N Hsu… - Science, 2001 - science.org
ME Gorre, M Mohammed, K Ellwood, N Hsu, R Paquette, PN Rao, CL Sawyers
Science, 2001science.org
Clinical studies with the Abl tyrosine kinase inhibitor STI-571 in chronic myeloid leukemia
demonstrate that many patients with advanced stage disease respond initially but then
relapse. Through biochemical and molecular analysis of clinical material, we find that drug
resistance is associated with the reactivation of BCR-ABL signal transduction in all cases
examined. In six of nine patients, resistance was associated with a single amino acid
substitution in a threonine residue of the Abl kinase domain known to form a critical …
Clinical studies with the Abl tyrosine kinase inhibitor STI-571 in chronic myeloid leukemia demonstrate that many patients with advanced stage disease respond initially but then relapse. Through biochemical and molecular analysis of clinical material, we find that drug resistance is associated with the reactivation of BCR-ABL signal transduction in all cases examined. In six of nine patients, resistance was associated with a single amino acid substitution in a threonine residue of the Abl kinase domain known to form a critical hydrogen bond with the drug. This substitution of threonine with isoleucine was sufficient to confer STI-571 resistance in a reconstitution experiment. In three patients, resistance was associated with progressiveBCR-ABL gene amplification. These studies provide evidence that genetically complex cancers retain dependence on an initial oncogenic event and suggest a strategy for identifying inhibitors of STI-571 resistance.
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