Abstract
ABL tyrosine kinase inhibitors (TKI) like Imatinib, Dasatinib and Nilotinib are the gold standard in conventional treatment of CML. However, the emergence of resistance remains a major problem. Alternative therapeutic strategies of ABL TKI-resistant CML are urgently needed. We asked whether dual inhibition of BCR-ABL and Aurora kinases A-C could overcome resistance mediated by ABL kinase mutations. We therefore tested the dual ABL and Aurora kinase inhibitors PHA-739358 and R763/AS703569 in Ba/F3- cells ectopically expressing wild type (wt) or TKI-resistant BCR-ABL mutants. We show that both compounds exhibited strong anti-proliferative and pro-apoptotic activity in ABL TKI resistant cell lines including cells expressing the strongly resistant T315I mutation. Cell cycle analysis indicated polyploidisation, a consequence of continued cell cycle progression in the absence of cell division by Aurora kinase inhibition. Experiments using drug resistant variants of Aurora B indicated that PHA-739358 acts on both, BCR-ABL and Aurora Kinase B, whereas Aurora kinase B inhibition might be sufficient for the anti-proliferative activity observed with R763/AS703569. Taken together, our data demonstrate that dual ABL and Aurora kinase inhibition might be used to overcome ABL TKI resistant CML.
Highlights
Chronic myeloid leukemia (CML) is a neoplastic disease of hematopoietic stem cells triggered by the oncogene BCR-ABL
Sensitivity of individual BCR-ABL mutants to PHA-739358 and R763/AS703569 did not correlate with the degree of resistance to IM, and the highly imatinib resistant BCR-ABL/T315I mutation displayed similar dose-response compared to BCR-ABL wt cells
Around 25% of patients treated with Imatinib do not respond to treatment or relapse after initial response to Imatinib [95, 96]. 2nd generation ABL-kinase inhibitors such as Nilotinib, Dasatinib, and Bosutinib proved to be effective against a variety of Imatinib-resistant BCR-ABL mutations, but are ineffective against the BCR-ABL T315I mutation [97,98,99]
Summary
Chronic myeloid leukemia (CML) is a neoplastic disease of hematopoietic stem cells triggered by the oncogene BCR-ABL This fusion gene is the result of a reciprocal translocation between chromosomes 9 and 22 and characterized by constitutively activation of the BCR-ABL tyrosine kinase [1,2,3]. Several mechanisms leading to IM resistance have been characterized during the last years: most commonly, mutations in the BCR/ABL domain confer IM resistance, either by altering IM binding characteristics or through indirect modulation of kinase function, which are often associated with secondary (acquired) resistance [19]. A functional cross-talk between Aurora A and the p53- and p73-dependent apoptotic pathway in cancer cells was reported [61]
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