Abstract
Abelson murine leukemia viral oncogene homolog (ABL) tyrosine kinase inhibitors (TKIs) have been shown to be effective for treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia patients. However, resistance to ABL TKIs can develop as a result of breakpoint cluster region-ABL point mutations. Aurora kinases regulate many processes associated with mitosis. In this study, we investigated whether inhibiting Aurora kinase can reduce the viability of Ph+ leukemia cells. Treatment with the Aurora kinase A inhibitor alisertib blocked Ph+ leukemia cell proliferation and Aurora kinase A phosphorylation; it also induced G2/M-phase arrest and increased the intracellular levels of reactive oxygen species. Combined treatment of Ph+ cells with ABL TKIs and alisertib was cytotoxic, with the fraction of senescent cells increasing in a time- and dose-dependent manner. Aurora A gene silencing suppressed cell proliferation and enhanced ABL TKI efficacy. In a mouse xenograft model, co-administration of ponatinib and alisertib enhanced survival and reduced tumor size; moreover, the treatments were well tolerated by the animals. These results indicate that inhibiting Aurora kinase can enhance the cytotoxic effects of ABL TKIs and is, therefore, an effective therapeutic strategy against ABL TKI-resistant cells, including those with the T315I mutation.
Highlights
Chronic myeloid leukemia (CML) is a myelo proliferative neoplasm characterized by cytogenetic aberration, namely, the translocation of the Philadelphia chromosome (Ph) [1], which generates a breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL1) fusion oncogene that encodes the BCR-ABL oncoprotein [2]
We found that Aurora A was phosphorylated in K562 and Ba/F3 T315I cells and that this was reduced in a dose-dependent manner by treatment with alisertib for 48 h (Figure 1A)
Immunoblot analysis revealed that imatinib or ponatinib and alisertib treatment increased caspase 3 and poly (ADPribose) polymerase (PARP) activity and reduced Crk-L phosphorylation in K562 and Ba/F3 T315I cells (Figure 2C). These results indicate that the combination of ABL tyrosine kinase inhibitors (TKIs) and Aurora kinase inhibitor is effective against Ph+ leukemia cells, including those with the T315I mutation
Summary
Chronic myeloid leukemia (CML) is a myelo proliferative neoplasm characterized by cytogenetic aberration, namely, the translocation of the Philadelphia chromosome (Ph) [1], which generates a breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL1) fusion oncogene that encodes the BCR-ABL oncoprotein [2]. Treatment options for CML include ABL tyrosine kinase inhibitors (TKIs) such as imatinib, which has been shown to be effective in patients [3]. CML patients with T315I mutation exhibit a reduced response to ABL TKIs, including the secondgeneration drugs nilotinib, dasatinib, and bosutinib [6]. Ponatinib ( known as AP24534) is an oral multitarget third-generation TKI [7] that can overcome imatinib resistance due to T315I mutation. Ponatinib is effective against heavily pretreated resistant CML and in one-third of patients in the accelerated or blastic phases of the disease [8]. In a clinical trial, only 62% of refractory CML patients exhibited a cytogenetic response to ponatinib treatment. New therapeutic approaches are needed to overcome ABL TKI resistance and improve the outcome of Ph-positive (Ph+) leukemia patients
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