Pharmacogenetic profiling of Aurora kinase B is associated with overall survival in metastatic colorectal cancer

Abstract

Aurora kinases are conserved eukaryotic serine-threonine kinases, which serve as key regulators of mammalian mitosis. Several studies revealed a distinct correlation between inaccurate chromosome segregation, leading to chromosomal number instability, cancer progression and poor outcome. The aim of this study was to investigate the correlation of Aurora kinases A (AURKA) and B (AURKB) with overall survival (OS) by quantifying gene expression analysis and evaluation of single-nucleotide polymorphisms (SNPs) in human colorectal cancer samples and assessing the associations with clinicopathological features. We evaluated intratumoral gene expression levels and SNPs of AURKA and -B from 41 patients with metastatic colorectal cancer (mCRC). Patients with a high expression level of AURKB (41.28) lived significantly shorter (n ¼ 11, median OS ¼ 6.4 months, 95% confidence interval (CI): 3.0-14.5 months) compared with patients with a low expression level (p1.28) (n ¼ 30, median OS ¼ 18.4 months, 95% CI: 14.7-27.8 months, P ¼ 0.026, Wald's test). Patients harboring any G-allele in AURKB 885A4G showed a significantly decreased OS (P ¼ 0.05, log-rank test). We did not find any associations with clinicopathological variables and AURKA gene expression levels. Our results suggest a potential role for AURKB inhibition in patients with mCRC; thereby supporting its potential role as a target in mCRC.

Aurora B: A New Prognostic Marker and Therapeutic Target in Cancer

“…In human colorectal cancer samples the correlation of Aurora B expression with overall survival was also evaluated, showing that patients with a high expression level of Aurora B lived significantly shorter compared with patients with low expression levels. Furthermore, single-nucleotide polymorphisms analysis showed that patients harboring G-allele in 885A>G showed a significantly decreased overall survival [122]. These studies suggest that Aurora B expression could be used as a predictor of aggressive lesions and as prognostic marker.…”

“…Hesperadin has IC 50 s values in the range of 1.2 μM to A>10 μM for cdk1/cyclin B or cdk2/cyclin E, respectively. The inhibitor inserts into the ATP binding pocket of both Aurora A and Aurora B [122,123,125].…”

Aurora B expression modulates paclitaxel response in non-small cell lung cancer

“…Aurora B kinase is an important contributor to the mitotic spindle assembly and its overexpression in human cancer has been frequently reported (Sorrentino et al , 2005; Lin et al , 2010; Pohl et al , 2011), therefore attracting significant interest in both cancer biology and therapeutics. In this study, we hypothesised that Aurora B activity may be implicated in modulating cellular response to taxanes, due to its role in mitotic spindle function, which is the target of these compounds.…”

Biological Characterization of TAK-901, an Investigational, Novel, Multitargeted Aurora B Kinase Inhibitor

“…Aurora A and B are overexpressed in many human cancers and are associated with poor prognosis, progression, and genetic instability (2,4,5,(11)(12)(13), making them attractive therapeutic targets. In vitro studies suggest that elevated Aurora A may promote oncogenesis (14,15), and its overexpression is associated with chromosome instability and clinically aggressive disease (5,15,16).…”