Aurora kinase inhibitors--rising stars in cancer therapeutics?

Abstract

Standard therapeutic approaches of cytotoxics and radiation in cancer are not only highly toxic, but also of limited efficacy in treatment of a significant number of cancer patients. The molecular analysis of the cancer genomes have shown a remarkable complexity and pointed to key genomic and epigenomic alterations in cancer. These discoveries are paving the way for targeted therapy approaches. However, although there are a large number of potential targets, only a few can regulate key cellular functions and intersect multiple signaling networks. The Aurora kinase family members (A, B, and C) are a collection of highly related and conserved serine-threonine kinases that fulfill these criteria, being key regulators of mitosis and multiple signaling pathways. Alterations in Aurora kinase signaling are associated with mitotic errors and have been closely linked to chromosomal aneuploidy in cancer cells. Several studies have shown amplification and/or overexpression of Aurora kinase A and B in hematologic malignancies and solid tumors. Over the past several years, Aurora kinases have become attractive targets. Several ongoing clinical trials and bench-based research are assessing the unique therapeutic potential of Aurora-based targeted therapy.

Figure 1

Schematic diagram of Aurora-A, -B, & -C kinase domains. N & C terminal domains contain most of the regulatory sequences. The central domain consists of catalytic kinase domain and activation loop. D-Box at the c-terminal domain is the destruction box. Brown box = Activation loop; Black box = destruction box at C terminus; Light green box = destruction box at N terminus; Light green box = Kinase domain.

Figure 2

Overview of the different effects that are observed upon over-expression and/or amplification of AURKA.

Figure 3

Schematic representation of AURKA interactions. AURKA over-expression inhibits p53 family members and suppresses apoptosis and cell cycle arrest. AURKA interacts directly with p53 by phosphorylating it at Ser215 (34) and 315 (35) causing its degradation through MDM2 or inactivating it at transcription level, respectively. AURKA regulates p73 and its downstream targets (37). It also up-regulates the PI3 kinase pathway that enhances cell survival and proliferation either directly interacting with GSK-3β (41) or by regulating AKT (36, 75).