Synergistic effects of proteasome inhibitor carfilzomib in combination with tyrosine kinase inhibitors in imatinib-sensitive and -resistant chronic myeloid leukemia models

Crawford, L.J., Chan, E.T., Aujay, M., Holyoake, T., Melo, J.V., Jorgensen, H. , Suresh, S., Walker, B. and Irvine, A.E. (2014) Synergistic effects of proteasome inhibitor carfilzomib in combination with tyrosine kinase inhibitors in imatinib-sensitive and -resistant chronic myeloid leukemia models. Oncogenesis, 3(3), e90. (doi: 10.1038/oncsis.2014.3) (PMID:24590311) (PMCID:PMC3940921)

Abstract

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Jorgensen, Dr Heather and Holyoake, Professor Tessa
• Authors: Crawford, L.J., Chan, E.T., Aujay, M., Holyoake, T., Melo, J.V., Jorgensen, H., Suresh, S., Walker, B., and Irvine, A.E.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Oncogenesis
• Publisher: Nature Publishing Group
• ISSN: 2157-9024
• ISSN (Online): 2157-9024
• Copyright Holders: Copyright © 2014 Macmillan Publishers Limited
• First Published: First published in Oncogenesis 3(3):e90
• Publisher Policy: Reproduced under a Creative Commons License