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  • The take home message here

    2023-11-18

    The take-home message here is that, although Aurora A phosphorylated on T288 is the activated isoform of Aurora A, measuring the level of phosphorylation of T288 does not reflect Aurora A kinase activity (Figure 5). What would be the most appropriate readout for an in vivo Aurora A kinase activity measurement? Although the Aurora A substrate LATS2 phosphorylated on Ser 83 has been reported to give good data, a comparison with an Aurora B substrate is need, and histone H3 phosphorylated on Ser 28 would be a suitable choice. Antiphosphoantibodies are also commercially available for both substrates [56].
    Concluding Remarks The development of protein kinase inhibitors to be used in cancer treatments is a long, expensive process. The cost of Phase III trial failures was recently evaluated [99] and the authors observed that cancer trials lead to failure more frequently than those for other diseases. Based on conference presentations at a European Center for Pharmaceutical Medicine seminar, the authors compiled a list of ‘drivers of failure’. These included inadequate basic science, flawed study design, suboptimal dose selection, flawed data collection and analysis, and problems with study operation [99]. In the case of Aurora A, basic science problems may be most responsible for trial failures, since the different functions of the kinase are not yet fully understood (see Outstanding Questions). It has become increasingly obvious that Aurora A activity is not just restricted to centrosome maturation and bipolar spindle assembly. How does Aurora A control acetylcholine chloride synthesis progression? The Aurora A community must now concentrate its efforts on understanding the functions of the kinase during different stages of interphase [100]. More importantly, how does Aurora A deregulation trigger carcinogenesis? In a complex organism, too much Aurora A is no good, but not enough is not good either. It should now be considered that Aurora A has cell type-specific functions. Cells can be polarized or not; cell division can be symmetric or asymmetric, can go from one mode of division to the other, and can lead to proliferation, differentiation, or stem cell renewal. In all these examples, there are specific functions and substrates for Aurora A; instead of targeting the kinase activity of Aurora-A, targeting only one of its substrates could be a way to inhibit one of its specific functions. However, when Aurora A inhibition is used as a part of cancer treatment, what are the consequences on the whole organism? Given its pleiotropy, direct inhibition of the kinase activity results in multiple adverse effects; thus, the inhibition of a specific substrate phosphorylation might lead to less-dramatic adverse effects. Since cancer research is and will remain a priority, financial support of basic science is crucial to improve the chances of success and transfer to the clinic. Isaac Newton said: ‘To explain all nature is too difficult a task for any one man or even for any one age. ‘Tis much better to do a little with certainty, & leave the rest for others that come after you, than to explain all things by conjecture without making sure of any thing.’ The development of effective and safe inhibitors depends on the knowledge of the target obtained through active exploration of fundamentals: ‘In order to beat your enemy, you must first know your enemy’ (The Art of War, Sun Tzu).
    Acknowledgments We thank Stéphanie Le Bras and Juliana Berland for suggestions and critical review of the manuscript. Work by C.P.’s team is supported by the Université of Rennes 1, the CNRS, and the Ligue Nationale Contre le Cancer (LNCC) ‘Équipe labellisée 2014.’ The PhD work of A.P.D. (2016-2018) and L.V. (2014-2017) is supported by grants from the LNCC and the Bretagne region; that of O.G. was financed by the Fonds de Recherche en Santé de Québec and the Fondation pour la Recherche Médicale.