Aurora Kinase Inhibition as a Novel Therapeutic Approach for the Treatment of Refractory Pediatric and Infant Leukemia.

摘要

Leukemia is the most common pediatric malignancy, consitituting more than 30% of all childhood cancers. Although cure rates have improved greatly, approximately one in four children relapse and survival rates post relapse are very low. Given this, more effective and innovative therapeutic strategies are needed in order to improve prognosis. Aurora kinases, a family of serine/threonine kinases essential for the regulation of several mitotic processes, have been identified as potential targets for cancer therapeutics. Elevated expression of Aurora kinases has been determined in several malignancies and is associated with aberrant mitotic activity, aneuploidy, alterations in chromosomal structure and genome instability. Based on this, a panel of Aurora kinase inhibitors was tested against pediatric leukemia cells and demonstrated variable cytotoxicity, the induction of apoptosis and changes in Aurora kinase activity. The dual Aurora-A/B inhibitor AT9283 was selected for further investigation, as it also targets FLT3, Jak2 and c-Abl, which are important in leukemogenesis. AT9283 promoted a polyploid phenotype, inhibited pathways involved in growth and survival and displayed synergistic activity with novel and conventional therapeutics. Of these therapeutics, ABT-737, a B--cell lymphoma 2 inhibitor, and BI 6727, a Polo-like kinase inhibitor, promoted increased Aurora kinase phosphorylation. Similarly, Aurora kinase inhibition promoted increased Bcl-2 phosphorylation and increased Plk-1 expression and activity. Furthermore, ABT-737 and BI 6727 displayed synergistic activity with several Aurora kinase inhibitors. This study establishes the effects and potential mechanisms of Aurora kinase inhibition on pediatric leukemia in vitro both as single agents and in combination with novel and conventional therapeutics targeting pathways involved in apoptosis and mitosis.