2007
DOI: 10.1182/blood-2006-10-054098
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Inhibition of heat shock protein 90 prolongs survival of mice with BCR-ABL-T315I–induced leukemia and suppresses leukemic stem cells

Abstract: IntroductionThe human Philadelphia chromosome (Ph) arises from a translocation between chromosomes 9 and 22 [t(9;22)(q34;q11)]. 1 The resulting chimeric BCR-ABL oncogene encodes a constitutively activated, oncogenic tyrosine kinase that induces chronic myeloid leukemia (CML) and B-cell acute lymphoblastic leukemia (B-ALL). The BCR-ABL TKI, imatinib mesylate, induces a complete hematologic and cytogenetic response in the majority of chronicphase CML patients, 2 but is unable to completely eradicate BCR-ABL-expr… Show more

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Cited by 142 publications
(151 citation statements)
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“…Previous reports from others showed that imatinib enhanced the cytotoxic effect of Hsp90 inhibitors. 29,38 We have also found a similar combinatory effect (see the effects at a fixed dose of GA in For personal use only. on May 12, 2018.…”
Section: Discussionsupporting
confidence: 60%
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“…Previous reports from others showed that imatinib enhanced the cytotoxic effect of Hsp90 inhibitors. 29,38 We have also found a similar combinatory effect (see the effects at a fixed dose of GA in For personal use only. on May 12, 2018.…”
Section: Discussionsupporting
confidence: 60%
“…T315I was found to bind Bag1 more strongly than the wt, which correlates with the sensitivity of Hsp90 inhibitors for BCR-ABL degradation and CML mice with the mutant. 8,29 These informations suggest that imatinib binding induces structural maturation of BCR-ABL to which Bag1 can no longer bind, and the T315I mutant is presumed to be less tightly bound to Hsp90 than the wt. The ABL kinase domain bound to imatinib may escape its degradation for the time being.…”
Section: Discussionmentioning
confidence: 99%
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“…Elimination of mutant BCR-ABL (T315I) kinase seems to be more effective therapeutic strategy for treating BCR-ABL-induced leukemia than the inhibition of BCR-ABL (T315I) kinase activity. Indeed, combination treatment with Hsp90 inhibitor IPI-504 and imatinib was more effective than either treatment alone in prolonging survival of mice simultaneously bearing both wild-type and T315I leukemic cells (131). Simultaneous exposure of BaF3 cells expressing BCR-ABL mutants including T315I to AUY922 and nilotinib was more effective at reducing the outgrowth of resistant cell clones as well as at survival prolongation of mice transplanted with mixture of BaF3 cells expressing wild-type BCR-ABL and mutant forms (132).…”
Section: Combination Of Hsp90 Inhibitor With Second Therapymentioning
confidence: 96%
“…122 Novel Hsp 90 inhibitors, such as IPI-504 will decrease the expression of the mutant BCR-ABL protein, although it should be kept in mind that the Hsp 90 inhibitors affect many proteins including Raf and Akt. 123 Combinations of MEK and dasatinib inhibitors may be effective in the treatment of imatinib-resistant patients harboring certain BCR-ABL mutations (for example, E225K, M351T). Unfortunately, this combination was not effective against imatinib-resistant cells with the T315I mutation.…”
Section: Targeting Imatinib-resistant CMLmentioning
confidence: 99%