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Blood, 15 July 2007, Vol. 110, No. 2, pp. 678-685.
Prepublished online as a Blood First Edition Paper on March 29, 2007; DOI 10.1182/blood-2006-10-054098.
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NEOPLASIA
Inhibition of heat shock protein 90 prolongs survival of mice with BCR-ABL-T315I–induced leukemia and suppresses leukemic stem cells
Cong Peng1,
Julia Brain2,
Yiguo Hu1,
Ami Goodrich1,
Linghong Kong1,
David Grayzel2,
Roger Pak2,
Margaret Read2, and
Shaoguang Li1
1 The Jackson Laboratory, Bar Harbor, ME;
2 Infinity Pharmaceuticals, Cambridge, MA
Development of kinase domain mutations is a major drug-resistance mechanism for tyrosine kinase inhibitors (TKIs) in cancer therapy. A particularly challenging example is found in Philadelphia chromosome–positive chronic myelogenous leukemia (CML) where all available kinase inhibitors in clinic are ineffective against the BCR-ABL mutant, T315I. As an alternative approach to kinase inhibition, an orally administered heat shock protein 90 (Hsp90) inhibitor, IPI-504, was evaluated in a murine model of CML. Treatment with IPI-504 resulted in BCR-ABL protein degradation, decreased numbers of leukemia stem cells, and prolonged survival of leukemic mice bearing the T315I mutation. Hsp90 inhibition more potently suppressed T315I-expressing leukemia clones relative to the wild-type (WT) clones in mice. Combination treatment with IPI-504 and imatinib was more effective than either treatment alone in prolonging survival of mice simultaneously bearing both WT and T315I leukemic cells. These results provide a rationale for use of an Hsp90 inhibitor as a first-line treatment in CML by inhibiting leukemia stem cells and preventing the emergence of imatinib-resistant clones in patients. Rather than inhibiting kinase activity, elimination of mutant kinases provides a new therapeutic strategy for treating BCR-ABL–induced leukemia as well as other cancers resistant to treatment with tyrosine kinase inhibitors.
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