The Aurora kinase family

By Mark Comer

Aurora kinases are serine/threonine kinases canonically involved in regulation of mitosis and cell division. Their key functions involve regulation of spindle assembly, segregation of chromosomes, and cytokinesis. Additional non-canonical functions are the subject of ongoing research and potentially include interactions with prominent tumour suppressors such as p53 (Sasai et al, 2016) As a family of highly conserved proteins will important regulatory functions (Tang et al, 2017), they have strong associations with cancer and tumour development. Overexpression or mutation of Aurora kinases is present in a wide variety of cancers, highlighting its potential significance in transformation. As a recent discovery, Aurora kinase inhibitors are currently in pre-clinical development and undergoing clinical trials as another tool to target cancer (Kollareddy et al, 2008).

The family is composed of three kinases: Aurora A (AURKA), Aurora B (AURKB), and Aurora C (AURKC). Each member has a distinct function, despite high sequence identity. AURKA is associated with spindles during mitosis and is regulated by phosphorylation, AURKB is defined as a chromosomal ‘passenger protein’ and regulates microtubule activity, chromatid separation, and phosphorylation of histones, while AURKC’s functions are not well defined (Carmena & Earnshaw, 2003). These functional differences are determined by the N-terminal amino acid domains which are unique for each member (Goldenson & Crispino, 2015). These functional differences extend such that AURKA has characterised oncogenic activity whilst AURKB does not (Bischoff et al, 1998). Interestingly, AURKA and AURKB demonstrate some level of functional redundancy, where AURKA has been shown to phosphorylate AURKB substrates in vitro (Carmena et al, 2009).  The most important structural feature is the regulatory “T-loop residue”, where autophosphorylation of threonine is necessary for any of the Aurora kinases to function. In AURKA this autophosphorylation is catalysed by the binding of TPX2, a spindle assembly factor, driving a conformational change in the kinase that also allows it to target mitotic spindles (Fu et al, 2007). AURKB is regulated by the chromosomal passenger complex, a ‘master regulator of mitosis’. Both are degraded by the APC/C in late mitosis.  Regulation also occurs on the transcript level, notably p53 regulates expression of potent inhibitors of AURKA. Despite their high similarity, AURKA and AURKB do not have many shared regulators or substrates, indicating very precise regulation. This could potentially explain the prevalence of abnormal AURKA activity in p53 deficient tumours (Carmena et al, 2009).

Although both AURKA and AURKB have well characterised functions in controlling and regulating the cell cycle, their association with tumorigenesis is not well defined. Overexpression of AURKA has been shown to induce transformation in in vitro studies but did not produce malignancy in mouse models (Zhang et al, 2004). One proposed mechanism underlying AURKA’s supposed oncogenic activity is the presence of multipolar or monopolar spindles leading to genomic instability. Aberrant AURKA can drive activation of the NFƙB pathway (Tang et al, 2017) and disrupt apoptosis by upregulating Bcl-2 and downregulating Bax (Huang et al, 2008) and Bim (Moustafa-Kemal et al, 2013). Furthermore, additional non-canonical functions of AURKA include upregulation of transcription factors known to drive the epithelial to mesenchymal transition (EMT) such as SLUG (Fenouille et al, 2012). AURKA overexpression is additionally protective against pharmaceutical agents that target spindle assembly, such as paclitaxel which typically triggers spindle checkpoint activation and is ineffective in cells with high AURKA activity (Goldenson & Crispino, 2015). AURKA also phosphorylates and regulates p53, increased AURKA-mediated p53 degradation is another proposed mechanism for tumorigenesis (Goldenson & Crispino, 2015).  AURKB’s role is more complicated, both overexpression and ablation results in polyploidy, its role and potential mechanism in driving transformation is not well understood. The importance of Aurora kinases and potential mechanisms of driving cancer development remains a subject of debate and ongoing research.

Therapeutic approaches targeting AURKs have not has as much success as other drugs that target more well characterised oncogenic kinases such as Bcr-abl.  AURKA activation has been implicated in a variety of resistances: against cisplatin and anti-ER-α therapies in breast cancer and EGFR agents in lung cancer, as well as resistance to radiotherapies (Tang et al, 2017).  Aside from directly targeting AURKs, overexpression of AURKA correlates strongly with prognosis, and thus Aurora kinases are a potential novel biomarker to indicate resistance to therapies. Work carried out in vitro has shown effective suppression of cell growth, proliferation, and migration (Diaz et al, 2012). Combination therapies with other inhibitors and drugs has shown great promise in overcoming resistance (Du et al, 2021), including in combination with second-generation Bcr-abl inhibitors nilotinib and dasatinib. The most promising application for Aurora kinase inhibitors appears to be in combination with well-established pharmaceutical agents. Despite this, toxicity of the inhibitors against normal cells represents a significant hurdle to wider clinical application. Ongoing research to tackle toxicity in normal cells and to enhance delivery (using nano-particle approaches) continues.

In summary, both canonical and non-canonical functions of Aurora kinases have strong associations with cancer. However, clear mechanisms that drive cancer progression and the significance of the myriad of interactions with tumour suppressors and oncogenes remain to be elucidated. The issue of high toxicity remains the most significant obstacle to drug development. Nonetheless, the Aurora kinase family is a potent addition to the growing list of both predictive biomarkers and potential therapeutic targets in cancer.


Sasai, K., Treekitkarnmongkol, W., Kai, K., Katayama, H. and Sen, S., 2016. Functional significance of aurora kinases–p53 protein family interactions in cancer. Frontiers in oncology, 6, p.247.

Tang, A., Gao, K., Chu, L., Zhang, R., Yang, J. and Zheng, J., 2017. Aurora kinases: novel therapy targets in cancers. Oncotarget, 8(14), p.23937.

Kollareddy, M., Dzubak, P., Zheleva, D. and Hajduch, M., 2008. Aurora kinases: structure, functions and their association with cancer. Biomedical Papers of the Medical Faculty of Palacky University in Olomouc, 152(1).

Carmena, M. and Earnshaw, W.C., 2003. The cellular geography of aurora kinases. Nature reviews Molecular cell biology, 4(11), pp.842-854.

Goldenson, B. and Crispino, J.D., 2015. The aurora kinases in cell cycle and leukemia. Oncogene, 34(5), pp.537-545.

Bischoff, J.R., Anderson, L., Zhu, Y., Mossie, K., Ng, L., Souza, B., Schryver, B., Flanagan, P., Clairvoyant, F., Ginther, C. and Chan, C.S., 1998. A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers. The EMBO journal, 17(11), pp.3052-3065.

Carmena, M., Ruchaud, S. and Earnshaw, W.C., 2009. Making the Auroras glow: regulation of Aurora A and B kinase function by interacting proteins. Current opinion in cell biology, 21(6), pp.796-805.C

Fu, J., Bian, M., Jiang, Q. and Zhang, C., 2007. Roles of Aurora kinases in mitosis and tumorigenesis. Molecular Cancer Research, 5(1), pp.1-10.

Zhang, D., Hirota, T., Marumoto, T., Shimizu, M., Kunitoku, N., Sasayama, T., Arima, Y., Feng, L., Suzuki, M., Takeya, M. and Saya, H., 2004. Cre-loxP-controlled periodic Aurora-A overexpression induces mitotic abnormalities and hyperplasia in mammary glands of mouse models. Oncogene, 23(54), pp.8720-8730.

Huang, X.F., Luo, S.K., Xu, J., Li, J., Xu, D.R., Wang, L.H., Yan, M., Wang, X.R., Wan, X.B., Zheng, F.M. and Zeng, Y.X., 2008. Aurora kinase inhibitory VX-680 increases Bax/Bcl-2 ratio and induces apoptosis in Aurora-A-high acute myeloid leukemia. Blood, The Journal of the American Society of Hematology, 111(5), pp.2854-2865.

Moustafa-Kamal, M., Gamache, I., Lu, Y., Li, S. and Teodoro, J.G., 2013. BimEL is phosphorylated at mitosis by Aurora A and targeted for degradation by β TrCP1. Cell Death & Differentiation, 20(10), pp.1393-1403.

Fenouille, N., Tichet, M., Dufies, M., Pottier, A., Mogha, A., Soo, J.K., Rocchi, S., Mallavialle, A., Galibert, M.D., Khammari, A. and Lacour, J.P., 2012. The epithelial-mesenchymal transition (EMT) regulatory factor SLUG (SNAI2) is a downstream target of SPARC and AKT in promoting melanoma cell invasion. PloS one, 7(7), p.e40378.

Diaz, R.J., Golbourn, B., Shekarforoush, M., Smith, C.A. and Rutka, J.T., 2012. Aurora kinase B/C inhibition impairs malignant glioma growth in vivo. Journal of neuro-oncology, 108(3), pp.349-360.

Du, R., Huang, C., Liu, K., Li, X. and Dong, Z., 2021. Targeting AURKA in Cancer: molecular mechanisms and opportunities for Cancer therapy. Molecular Cancer, 20(1), pp.1-27.

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