Targeting AURKA in Cancer: molecular mechanisms and opportunities for Cancer therapy

Abstract

Aurora kinase A (AURKA) belongs to the family of serine/threonine kinases, whose activation is necessary for cell division processes via regulation of mitosis. AURKA shows significantly higher expression in cancer tissues than in normal control tissues for multiple tumor types according to the TCGA database. Activation of AURKA has been demonstrated to play an important role in a wide range of cancers, and numerous AURKA substrates have been identified. AURKA-mediated phosphorylation can regulate the functions of AURKA substrates, some of which are mitosis regulators, tumor suppressors or oncogenes. In addition, enrichment of AURKA-interacting proteins with KEGG pathway and GO analysis have demonstrated that these proteins are involved in classic oncogenic pathways. All of this evidence favors the idea of AURKA as a target for cancer therapy, and some small molecules targeting AURKA have been discovered. These AURKA inhibitors (AKIs) have been tested in preclinical studies, and some of them have been subjected to clinical trials as monotherapies or in combination with classic chemotherapy or other targeted therapies.

Keywords: Aurora kinase a; Cancer; Combination therapy; Inhibitors; Regulators; Substrates.

Fig. 1

Expression of Aurora kinases in cancer. (A) Expression of Aurora kinases among various cancer types. (B) Comparison of the expression of Aurora kinases between tumor and normal tissues. The images and significance are from ULCAN database. * P < 0.05, ** P < 0.01, *** P < 0.001, NS: no significance

Fig. 2

Correlation between Aurora kinases expression and patient overall survival. Red text: gene expression had significant relation with survival; black text: gene expression had no significant relation with survival. The survival data are derived from ULCAN database. Samples were categorized into two groups for analysis: High AURKA expression (with TPM values above upper quartile); Low/Medium AURKA expression (with TPM values below upper quartile). * P < 0.05, ** P < 0.01, *** P < 0.001

Fig. 3

AURKA interactome and related signaling pathways. The interactome in the center is obtained through STRING database based on AURKA-interacted proteins mentioned in Table 1 and Table 2. The interactome around are enriched pathway proteins. The left bottom literal statements are the alternative names of the molecular

Fig. 4

An overview of AURKA-interacting proteins and AKIs. AURKA expression is regulated at transcriptional or post-transcriptional levels and AURKA activity is tightly controlled by numerous molecules. Once activated, AURKA interacts with and phosphorylates a wide variety of proteins serving as mitotic regulators, oncogenes or tumor suppressors. Selective AKIs and pan Aurora kinases inhibitors are developed and studied in preclinical or clinical evaluation