Therapeutic targeting of Aurora A kinase in Philadelphia chromosome-positive ABL tyrosine kinase inhibitor-resistant cells

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.