Abstract
Introduction: Based on its role as a mitotic regulatory kinase, overexpressed and associated with aneuploidy in cancer, small-molecule inhibitors have been developed for Aurora-A (AURKA) kinase. In preclinical and clinical assessments, these agents have shown efficacy in inducing stable disease or therapeutic response. In optimizing the use of Aurora-A inhibitors, it is critical to have robust capacity to measure the kinase activity of Aurora-A in tumors.
Areas covered: We provide an overview of molecular mechanisms of mitotic and non-mitotic activation of Aurora-A kinase, and interaction of Aurora-A with its regulatory partners. Typically, Aurora-A activity is measured by use of phospho-antibodies targeting an autophosphorylated T288 epitope. However, recent studies have identified alternative means of Aurora-A activation control, including allosteric regulation by partners, phosphorylation on alternative activating residues (S51, S98), dephosphorylation on inhibitory sites (S342) and T288 phosphorylation by alternative kinases such as Pak enzymes. Additional work has shown that the relative abundance of Aurora-A partners can affect the activity of Aurora-A inhibitors, and that Aurora-A activation also occurs in interphase cells.
Expert opinion: Taken together, this work suggests the need for comprehensive analysis of Aurora-A activity and expression of Aurora-A partners in order to stratify patients for likely therapeutic response.
Acknowledgments
The authors were supported by R21CA181287 and R01CA63366 (to EA Golemis), R01GM084453 (to RL Dunbrack Jr), and P30 CA006927 (to Fox Chase Cancer Center). We thank Ilya Serebriiskii for valuable comments on the paper.
Declaration of interest
The authors were supported by the NIH. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Notes
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