Aurora kinases in head and neck cancer

Abstract

In healthy cells, controlled activation of aurora kinases regulates mitosis. Overexpression and hyperactivation of aurora kinases A and B have major roles in tumorigenesis, and can induce aneuploidy and genomic instability. In squamous-cell carcinomas of the head and neck, overexpression of aurora kinase A is associated with decreased survival, and a reduction in aurora kinase A and aurora kinase B expression inhibits cell growth and increases apoptosis. In this Review, we provide an overview of the biological functions of aurora kinases in healthy cells and in cancer cells, and we review small studies and high-throughput datasets that particularly implicate aurora kinase A in the pathogenesis of squamous-cell carcinomas of the head and neck. Early phase trials are beginning to assess the activity of small-molecule inhibitors of aurora kinases. We summarise trials of aurora kinase inhibitors in squamous-cell carcinomas of the head and neck, and discuss directions for future drug combination trials and biomarkers to use with drugs that inhibit aurora kinases.

Figure 1. Localization and function of Aurora-A and Aurora-B

Representation of Aurora-A (red) and Aurora-B (purple) kinase association with intracellular structures during cell cycle. Association with partners of specific relevance for cancer are indicated in inset circles. DNA/chromatin is indicated in teal; the centrosome and mitotic spindle in gold. See text for details regarding functional interactions. CPC, Chromosomal passenger complex. Graphic representation adapted from http://en.wikipedia.org/wiki/File:Animal_cell_cycle.svg in Wikimedia Commons.

Figure 2. Expression and mutational profile of Aurora proteins in SCCHN tumors

A. Publicly available microarray data from the Gene Expression Omnibus (GEO) [51] and ArrayExpress (http://www.ebi.ac.uk/arrayexpress/) databases were used by Genevestigator portal https://genevestigator.com/[52] to generate expression meta-profiles, which make data highly comparable between different experiments. Expression levels of Aurora-A (AURKA) and Aurora-B (AURKB), and other genes noted in the text across a range of cancer types were plotted using Genevestigator software. X-axis, log2 scale. B. Analysis of the Head and Neck Squamous Cell Carcinoma subset of TCGA data[53] (from a provisional release of 310 samples) were analyzed using the cBio portal. [54] The displayed Oncoprint, generated by the cBio portal, shows individual samples as vertical columns, with the alterations on each gene as shown in the graphic legend embedded in the figure: not all specimens with only mutated p53, or with no mutations, are shown. High gene expression is defined as having a z score >2 based on reference (matched normal) sample population. IQR, interquartile range (defines expression of 25-75% of all genes) C. Kaplan-Meier plot comparing survival for high and low expression cohorts in regard to Aurora-A and Aurora-B, based on TCGA data.

Figure 3. A SCCHN network for Aurora-associated proteins

A network was generated around the Aurora-A (AURKA) and Aurora-B (AURKB) proteins was generated by the cBio portal [54] using data from Pathway Commons regarding protein-protein (HPRD), enzymatic (Reactome ) and pathway (NCI-Nature Pathway Interaction Database) interactions. Of all neighbors of the seed genes (AURKA & AURKB), the 50 most frequently altered in the SCCHN subset of TCGA data are shown. All proteins are identified by official gene symbol. Node coloring (white to red: low to high) reflects the combined frequency of all alterations for a given gene. Blue and green arrows represent enzyme-substrate interactions. The group of proteins circled by a dashed line represents a large group of coordinately regulated proteins found in a mitotic complex with Aurora-B at the centromere/kinetochore. Detailed information (i.e., copy number alterations, expression change, frequency of mutations) can be viewed for each gene in a network generated for AURKA and AURKB on http://www.cbioportal.org/.

Figure 4. Aurora combination therapies and interrelation of drug targets

Aurora-A (AURKA) and Aurora-B (AURKB) inhibitors (orange shading) block processes required for mitosis. Productive therapeutic combinations involve small molecules and antibodies targeting proteins influencing cell proliferation and survival signaling, or cytotoxics inducing DNA damage and mitotic checkpoints (drugs indicated in pink shading). See text for details.