Opposing Effects of Inhibitors of Aurora-A and EGFR in Autosomal-Dominant Polycystic Kidney Disease.

Anna S Nikonova,Louisa Eckman,Meghan C Kopp,Alexander Y Deneka,Erica A Golemis,Harvey H Hensley,Brian L Egleston

doi:10.3389/fonc.2015.00228

Abstract

Aurora-A kinase (AURKA) overexpression in numerous tumors induces aneuploidy, in part because of cytokinetic defects. Alisertib and other small-molecule inhibitors targeting AURKA are effective in some patients as monotherapies or combination therapies. Epidermal growth factor receptor (EGFR) pro-proliferative signaling activity is commonly elevated in cancer, and the EGFR inhibitor erlotinib is commonly used as a standard of care agent for cancer. An erlotinib/alisertib combination therapy is currently under assessment in clinical trials, following pre-clinical studies that indicated synergy of these drugs in cancer. We were interested in further exploring the activity of this drug combination. Beyond well-established functions for AURKA in mitotic progression, additional non-mitotic AURKA functions include control of ciliary stability and calcium signaling. Interestingly, alisertib exacerbates the disease phenotype in mouse models for autosomal-dominant polycystic kidney disease (ADPKD), a common inherited syndrome induced by aberrant signaling from PKD1 and PKD2, cilia-localized proteins that have calcium channel activity. EGFR is also more active in ADPKD, making erlotinib also of potential interest in this disease setting. In this study, we have explored the interaction of alisertib and erlotinib in an ADPKD model. These experiments indicated erlotinib-restrained cystogenesis, opposing alisertib action. Erlotinib also interacted with alisertib to regulate proliferative signaling proteins, albeit in a complicated manner. Results suggest a nuanced role of AURKA signaling in different pathogenic conditions and inform the clinical use of AURKA inhibitors in cancer patients with comorbidities.

Highlights

In its role as a mitotic regulator, Aurora-A kinase (AURKA) accumulates through G2 at the centrosome, becomes active at G2/M transition, and remains active through M phase as it translocates along the mitotic spindle to the midzone, with the bulk of AURKA degraded at the midbody at cytokinesis
Treatment with alisertib or alisertib plus erlotinib resulted in slower weight gain over 10 weeks in both wild type and Pkd1−/− groups, while erlotinib alone had no effect on weight gain (Figure 1B)
This study has established that the cystogenic activity of the AURKA inhibitor in autosomaldominant polycystic kidney disease (ADPKD) can be partially reversed by treatment with erlotinib, and for the first time showed that erlotinib itself has a potent activity in limiting cystic growth

Summary

Introduction

In its role as a mitotic regulator, Aurora-A kinase (AURKA) accumulates through G2 at the centrosome, becomes active at G2/M transition, and remains active through M phase as it translocates along the mitotic spindle to the midzone, with the bulk of AURKA degraded at the midbody at cytokinesis. Growth factor stimulation of quiescent ciliated cells induces NEDD9 expression and AURKA activation, leading to resorption of the cilium [25]. These latter activities were of particular interest, as they potentially informed some roles of AURKA relevant to cancer [26, 27] and connected AURKA activity to another pathological condition, autosomaldominant polycystic kidney disease (ADPKD)

Methods

Results

Conclusion