BCR-ABL point mutants isolated from patients with imatinib mesylate-resistant chronic myeloid leukemia remain sensitive to inhibitors of the BCR-ABL chaperone heat shock protein 90 Journal Article


Authors: Gorre, M. E.; Ellwood-Yen, K.; Chiosis, G.; Rosen, N.; Sawyers, C. L.
Article Title: BCR-ABL point mutants isolated from patients with imatinib mesylate-resistant chronic myeloid leukemia remain sensitive to inhibitors of the BCR-ABL chaperone heat shock protein 90
Abstract: Clinical resistance to imatinib mesylate is commonly observed in patients with advanced Philadelphia chromosome-positive (Ph+) leukemias. Acquired resistance is typically associated with reactivation of BCR-ABL due to kinase domain mutations or gene amplification, indicating that BCR-ABL remains a viable target for inhibition in these patients. Strategies for overcoming resistance can be envisioned through exploitation of other molecular features of the BCR-ABL protein, such as its dependence on the molecular chaperone heat shock protein 90 (Hsp90). To determine whether inhibition of Hsp90 could induce degradation of imatinib mesylate-resistant, mutant BCR-ABL proteins, hematopoietic cells expressing 2 mutant BCR-ABL proteins found in imatinib mesylate-resistant patients (T3151 and E255K) were examined for sensitivity to geldanamycin and 17-allylaminogeldanamycin (17-AAG). Both compounds induced the degradation of wild-type and mutant BCR-ABL and inhibited cell growth, with a trend indicating more potent activity against mutant BCR-ABL proteins. These data support clinical investigations of 17-AAG in imatinib mesylate-resistant Ph+ leukemias. © 2002 by The American Society of Hematology.
Keywords: controlled study; unclassified drug; human cell; antineoplastic agents; molecular genetics; protein domain; sensitivity analysis; gene targeting; imatinib; disease association; gene amplification; cell growth; protein degradation; protein binding; drug potency; drug resistance, neoplasm; chronic myeloid leukemia; pyrimidines; immunoreactivity; wild type; hematopoietic cell; heat shock protein 90; hsp90 heat-shock proteins; inhibition kinetics; bcr abl protein; piperazines; point mutation; fusion proteins, bcr-abl; philadelphia 1 chromosome; growth inhibition; geldanamycin; chaperone; gene isolation; genetic resistance; leukemia, myeloid, chronic; leukemia, myeloid, philadelphia-positive; humans; human; priority journal; article; 17 allylaminogeldanamycin
Journal Title: Blood
Volume: 100
Issue: 8
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2002-10-15
Start Page: 3041
End Page: 3044
Language: English
DOI: 10.1182/blood-2002-05-1361
PUBMED: 12351420
PROVIDER: scopus
DOI/URL:
Notes: Export Date: 14 November 2014 -- Source: Scopus
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MSK Authors
  1. Charles L Sawyers
    155 Sawyers
  2. Neal Rosen
    364 Rosen
  3. Gabriela Chiosis
    218 Chiosis