The potential role of Aurora kinase inhibitors in haematological malignancies

Abstract

Aurora kinases play an important role in the control of the cell cycle and have been implicated in tumourigenesis in a number of cancers. Among the haematological malignancies, overexpression of Aurora kinases has been reported in acute myeloid leukaemia, chronic myeloid leukaemia, acute lymphoblastic leukaemia, multiple myeloma, aggressive non-Hodgkin lymphoma and Hodgkin lymphoma. A large number of Aurora kinase inhibitors are currently in different stages of clinical development. In addition to varying in their selectivity for the different Aurora kinases, some also have activity directed at other cellular kinases involved in important molecular pathways in cancer cells. This review summarizes the biology of Aurora kinases and discusses why they may be good therapeutic targets in different haematological cancers. We describe preclinical data that has served as the rationale for investigating Aurora kinase inhibitors in different haematological malignancies, and summarize published results from early phase clinical trials. While the anti-tumour effects of Aurora kinase inhibitors appear promising, we highlight important issues for future clinical research and suggest that the optimal use of these inhibitors is likely to be in combination with cytotoxic agents already in use for the treatment of various haematological cancers.

Figure 1. Cellular localization of Aurora kinases A and B in mitosis

In G1, the levels of both Aurora A (green squares) and Aurora B (red circles) kinases are markedly reduced, but increase with different localization during M phase. In prophase, Aurora A is located around the centrosomes, whereas Aurora B is nuclear. In metaphase, Aurora A is on the microtubules near the spindle poles, whereas Aurora B is located in the inner centromere. In anaphase, most Aurora A is on the polar microtubules, but some might also be located in the spindle midzone. Aurora B is concentrated in the spindle midzone and at the cell cortex at the site of cleavage-furrow ingression. In cytokinesis, both kinases are concentrated in the midbody. Reprinted by permission from Nature Publishing Group: Nature Reviews Molecular Cell Biology 4, 842–854, Carmena & Earnshaw (2003).

Figure 2. Function of Aurora A during late G2 and mitosis

(A) In late G2, Aurora A autophosphorylates and also activates PLK1, which in turn promotes the binding of Aurora A to centrosomin. PLK1 is recruited to the centrosome by cenexin 1. While Aurora A can self-activate, its activity is enhanced by several cofactors, including TPX2 and BORA. Active PLK1 phosphorylates WEE1, a kinase that negatively regulates cyclin B-CDK1 complexes. The cell division cycle 25 (CDC25) phosphatases that antagonize WEE1 are largely inactive in G2. (B) Mitotic entry is triggered by a steep increase in cyclin B-CDK1 activity. On the centrosome, Aurora A and PLK1 promote recruitment and activation of CDC25B, which in turn, activates cyclin B-CDK1. Cyclin B–CDK1 complexes further phosphorylate WEE1 and BORA, which are then recognized by the F-box protein β-transducin repeat containing (β-TrCP) that promotes polyubiquitylation (Ub) and degradation of WEE1 and BORA. Freed of BORA, Aurora kinase A is then able to interact with TPX2, thus facilitating the role of the kinase in spindle assembly (see text). Green phosphates (P) are activating, red phosphates are inhibitory and yellow phosphates prime a protein for degradation. Reprinted by permission from Nature Publishing Group: Nature Reviews Cancer 10, 825–841, Lens et al (2010).

Figure 3. Aurora B regulation of kinetochore-microtubule interactions

The affinity of the microtubules to the kinetochore is affected by a phosphorylation gradient of Aurora B. (A) In prophase, Aurora B, present at the inner centromere, is in close proximity to the kinetochore due to a lack of tension allowing Aurora B to phosphorylate all components of the KMN network (comprising KNL1, MIS12 and NDC80 (also known as highly expressed in cancer [HEC1]), which serves as the main microtubule-binding unit at the kinetochore; consequently, the kinetochore has low affinity for microtubules. Similarly, non-bipolar attachment of microtubules to the kinetochore does not generate tension across the centromere, and therefore the kinetochore remains in close proximity to Aurora B and the KMN complex is phosphorylated by Aurora B. Also, phosphorylation of KNL1 by Aurora B prevents the binding of PP1γ (which dephosphorylates KMN substrates) to the kinetochore. Phosphorylation of KMN components and blocking of PP1γ binding to the kinetochore significantly reduce kinetochore affinity for microtubules. Attachment of the kinetochore to the microtubules, therefore, is broken, preventing chromatid separation until the appropriate attachments are reassembled. As the cell progresses through prometaphase (B) and metaphase (C), and when there is correct bipolar attachment of microtubules, tension is generated and the kinetochore is physically separated from Aurora B and PP1γ binding is not inhibited, resulting in dephosphorylation of the KMN components. Further, Aurora B also recruits the kinetochore-associated checkpoint kinase BURB1 where it is phosphorylated by PLK1, which in turn results in reduced Aurora B activity, also promoting attachment of microtubules to the kinetochore. Reprinted by permission from Nature Publishing Group: Nature Reviews Cancer 10, 825–841, Lens et al (2010).