Activation of Aurora kinase A (AURKA) plays an essential role in the control of mitosis progression, centrosome maturation/ separation and mitotic spindle function. AURKA has attracted a great deal of interest as a potential therapeutic target due to its overexpression in cancers. Inhibitors of Aurora kinases, such as MLN8237 and PHA-739358, have been developed15, but were found to be moderately effective in preclinical and clinical studies. These data suggest that a kinase-independent mechanism contributes to inhibitor insensitivity.
There is emerging evidence to suggest that AURKA also promotes cancer development through mechanisms independently of its kinase activity. Moreover, AURKA localizes to structures other than the mitotic apparatus during interphase to regulate neurite elongation and ciliary resorption, suggesting that AURKA possesses functions beyond its kinase activity, and that inhibition of Aurora kinase alone may not be sufficient to repress AURKA oncogenic functions.
Previous study shows that the tumor tissues display nuclear AURKA staining, which predicts a poorer clinical outcome in ovarian cancer. Conversely, cytoplasmic localized AURKA consistently fails to enhance the H-Ras-induced transformation in BALB/c 3T3 A31-1-1 cells21. These studies suggest an oncogenic role of nuclear AURKA that might be independent of its kinase activity.
Researchers show that AURKA translocates to the nucleus and causes distinct oncogenic properties in malignant cells by enhancing breast cancer stem cell (BCSC) phenotype. Unexpectedly, this function is independent of its kinase activity.
Instead, AURKA preferentially interacts with heterogeneous nuclear ribonucleoprotein K (hnRNP K) in the nucleus and acts as a transcription factor in a complex that induces a shift inMYC promoter usage and activates theMYC promoter.
Blocking AURKA nuclear localization inhibits this newly discovered transactivating function of AURKA, sensitizing resistant BCSC to kinase inhibition.
These findings identify a previously unknown oncogenic property of the spatially deregulated AURKA in tumorigenesis and provide a potential therapeutic opportunity to overcome kinase inhibitor resistance.