Abstract

The serine/threonine kinase Aurora A is a key regulator of mitosis. Its expression and activation are necessary for mitotic entry, centrosome maturation, and mitotic spindle assembly and function. Aurora A gene amplification and/or overexpression of its encoded protein has been observed in many types of human tumors and is hypothesized to promote genetic instability, a hallmark feature of malignant cells that contributes to disease progression and drug resistance. The central and obligatory role of Aurora A in mitosis and its dysregulation in cancer makes it an attractive target for therapeutic inhibition. MLN8237 is a novel orally available Aurora A inhibitor developed for cancer therapy by Millennium Pharmaceuticals that has entered Phase I trials in humans. We investigated the preclinical efficacy and mechanism of action of MLN8237 in models of chronic myeloid leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Sub-micromolar concentrations of MLN8237 potently inhibited the in vitro growth and survival of human CML and Ph+ ALL cell lines and primary cells derived from CML and Ph+ ALL patients. In vitro kinase assays demonstrated that MLN8237 effectively inhibits the activity of wildtype and drug-resistant mutant forms of BCR-ABL. Notably, MLN8237 possessed equipotent anticancer activity against Ba/F3 cells expressing wildtype (p210) BCR-ABL and the imatinib, nilotinib, dasatinib, and bosutinib-resistant mutant T315I form of BCR-ABL. Loss of function of the p53 tumor suppressor contributes to resistance to imatinib and many other anticancer agents. We assessed the potential impact of loss of p53 function on cellular sensitivity to MLN8237 by achieving stable shRNA-mediated p53 knockdown in Ba/F3 cells expressing p210 BCR-ABL. Impairment of p53 function did not significantly affect the anticancer activity of MLN8237, indicating that it may be an effective agents for patients with p53 defects. Daily oral administration of MLN8237 (20 mg/kg BID) to immunodeficient mice bearing xenografts of the K562 human CML blast crisis cell line was very well tolerated and significantly reduced tumor growth in vivo. Moreover, co-administration of MLN8237 and nilotinib resulted in significantly greater tumor growth inhibition than what was achieved by either single agent alone. These data suggest that MLN8237 is a promising new agent for the treatment of CML and Ph+ ALL patients that fail to respond to conventional therapy.

Disclosures: Ecsedy:Millennium Pharmaceuticals: Employment.

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