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Science 293 (5531): 876-880

Copyright © 2001 by the American Association for the Advancement of Science

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

Mercedes E. Gorre,13 Mansoor Mohammed,2 Katharine Ellwood,1 Nicholas Hsu,1 Ron Paquette,1 P. Nagesh Rao,2 Charles L. Sawyers13*

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 progressive BCR-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.

1 Department of Medicine,
2 Department of Pathology, and
3 Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA.
*   To whom correspondence should be addressed. E-mail: csawyers{at}mednet.ucla.edu

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