Solid Cancer Treatment With Aurora Kinase Inhibitors: Towards a Personalized Medicine

https://doi.org/10.1016/j.ebiom.2017.10.026 2352-3964/© 2017 The Author(s). Published by Elsevier B Several mitotic proteins, whose expression or function has been found deregulated in human solid neoplasms, are thought to play a critical role in tumor genetic instability, a hallmark of cancer (Hanahan and Weinberg, 2011; Otto and Sicinski, 2017). These include the three serine/threonine Aurora kinase family members (Aurora A, B and C), involved in centrosome maturation, chromosome segregation and cytokinesis (Carmena and Earnshaw, 2003; Carmena et al., 2012). The gene AURKA, encoding Aurora A, maps at the locus 20q13, frequently amplified in different cancer types. The gene AURKB, encoding Aurora B, is located at the locus 17p13, which harbours also the TP53 oncogene and often undergoes genetic aberrations in cancer resulting in the loss of p53 activity (Baldini et al., 2014). The upregulation of either Aurora A or B is thought to cause defects in chromosome segregation with consequent aneuploidy, and it has been shown to induce cell malignant transformation (Baldini et al., 2014). Furthermore, overexpression of Aurora kinases, observed in several cancer types, has been found to associate with a poor prognosis (Baldini et al., 2014; Tang et al., 2017; Kollareddy et al., 2012; Bavetsias and Linardopoulos, 2015). As a consequence, the Aurora kinases have been regarded as promising therapeutic targets for both solid and hematologic malignancies (Baldini et al., 2014; Tang et al., 2017; Kollareddy et al., 2012; Bavetsias and Linardopoulos, 2015). A number of either selective or pan-inhibitors of Aurora kinases have been developed over the last decade (Baldini et al., 2014; Tang et al., 2017; Kollareddy et al., 2012). However, despite the encouraging results in preclinical studies, clinical trials with different Aurora kinase inhibitors showed a limited efficacy against solid tumors, while higher response rates against hematologic malignancies were observed (Bavetsias and Linardopoulos, 2015). It has been speculated that such different outcome may be due to the higher homogeneity and higher proliferation rates observed in the hematologic malignancies relative to solid tumors (Bavetsias and Linardopoulos, 2015). Other possible causes of solid tumor resistance to aurora kinase inhibitors are emerging from preclinical studies (Kollareddy et al., 2012). Indeed, experiments performed on colon and pancreatic derived cell lines (SW620 andMiaPaca, respectively) treated for long period of time with the specific Aurora B inhibitor AZD1152, showed the development of clones of cancer cells in which drug accumulation in the cytoplasmwas drastically reduced following the strong