BCR-ABL point mutants isolated from patients with imatinib mesylate–resistant chronic myeloid leukemia remain sensitive to inhibitors of the BCR-ABL chaperone …

ME Gorre, K Ellwood-Yen, G Chiosis… - Blood, The Journal …, 2002 - ashpublications.org
ME Gorre, K Ellwood-Yen, G Chiosis, N Rosen, CL Sawyers
Blood, The Journal of the American Society of Hematology, 2002ashpublications.org
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 …
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 (T315I 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.
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