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:	http://www.scopus.com/inward/record.url?eid=2-s2.0-0037108448&partnerID=40&md5=ead1391c44c0c2fef329d353ae71497a
Notes:	Export Date: 14 November 2014 -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/66554