title: Synergistic effects of proteasome inhibitor carfilzomib in combination with tyrosine kinase inhibitors in imatinib-sensitive and -resistant chronic myeloid leukemia models.
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.
authors.affiliation: Department of Haematology, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
authors.forename: L J
authors.initials: LJ
authors.lastname: Crawford
authors.affiliation: Onyx Pharmaceuticals Inc., South San Francisco, CA, USA.
authors.forename: E T
authors.initials: ET
authors.lastname: Chan
authors.affiliation: Onyx Pharmaceuticals Inc., South San Francisco, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Aujay
authors.affiliation: Department of Experimental Haematology, Paul O'Gorman Leukaemia Research Centre, University of Glasgow, Glasgow, UK.
authors.forename: T L
authors.initials: TL
authors.lastname: Holyoake
authors.affiliation: 1] Department of Haematology, Centre for Cancer Biology, IMVS, Adelaide, South Australia, Australia [2] Department of Haematology, Imperial College London, London, UK.
authors.forename: J V
authors.initials: JV
authors.lastname: Melo
authors.affiliation: Department of Experimental Haematology, Paul O'Gorman Leukaemia Research Centre, University of Glasgow, Glasgow, UK.
authors.forename: H G
authors.initials: HG
authors.lastname: Jorgensen
authors.affiliation: Department of Haematology, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
authors.forename: S
authors.initials: S
authors.lastname: Suresh
authors.affiliation: School of Pharmacy, Queen's University Belfast, Belfast, UK.
authors.forename: B
authors.initials: B
authors.lastname: Walker
authors.affiliation: Department of Haematology, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
authors.forename: A E
authors.initials: AE
authors.lastname: Irvine