Journal
ONCOGENESIS
Volume 3, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/oncsis.2014.3
Keywords
chronic myeloid leukemia; imatinib resistance; tyrosine kinase inhibitor; carfilzomib
Categories
Funding
- Leukaemia Lymphoma Research UK
- Northern Ireland Leukaemia Research Fund
- Cancer Research UK
- Glasgow Experimental Cancer Medicine Centre
- NIHR Biomedical Research Centre Funding Scheme, UK
- Cancer Research UK [11008] Funding Source: researchfish
- Leukaemia & Lymphoma NI [R2029HAE, R2783CNR, R2043HAE, R2054CNR, R2031HAE] Funding Source: researchfish
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The tyrosine kinase inhibitor (TKI) imatinib has transformed the treatment and outlook of chronic myeloid leukemia (CML); however, the development of drug resistance and the persistence of TKI-resistant stem cells remain obstacles to eradicating the disease. Inhibition of proteasome activity with bortezomib has been shown to effectively induce apoptosis in TKI-resistant cells. In this study, we show that exposure to the next generation proteasome inhibitor carfilzomib is associated with a decrease in ERK signaling and increased expression of Abelson interactor proteins 1 and 2 (ABI-1/2). We also investigate the effect of carfilzomib in models of imatinib-sensitive and -resistant CML and demonstrate a potent reduction in proliferation and induction of apoptosis in a variety of models of imatinib-resistant CML, including primitive CML stem cells. Carfilzomib acts synergistically with the TKIs imatinib and nilotinib, even in imatinib-resistant cell lines. In addition, we found that the presence of immunoproteasome subunits is associated with an increased sensitivity to carfilzomib. The present findings provide a rational basis to examine the potential of carfilzomib in combination with TKIs as a potential therapy for CML, particularly in imatinib-resistant disease.
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