Inhibition of heat shock protein 90 prolongs survival of mice with BCR-ABL-T315I-induced leukemia and suppresses leukemic stem cells.
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.
Peng
Cong
C
The Jackson Laboratory, Bar Harbor, ME 04609, USA.
Brain
Julia
J
Hu
Yiguo
Y
Goodrich
Ami
A
Kong
Linghong
L
Grayzel
David
D
Pak
Roger
R
Read
Margaret
M
Li
Shaoguang
S
D019943:Amino Acid Substitution; D000818:Animals; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000473:pathology*; D007942:Leukemia, Experimental / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D051379:Mice; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D016019:Survival Analysis
D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl