Aurora Kinase Inhibition Overcomes Cetuximab Resistance in Squamous Cell Cancer of the Head and Neck

Abstract

Squamous cell cancer of the head and neck (SCCHN) is the sixth leading cause for cancer deaths worldwide. Despite extense knowledge of risk factors and pathogenesis about 50 percent of all patients and essentially every patient with metastatic SCCHN eventually die from this disease. We analyzed the clinical data and performed immunohistochemistry for Epidermal growth factor receptor (EGFR) and Aurora kinase A (Aurora-A) expression in 180 SCCHN patients. Patients characterized by elevated EGFR and elevated Aurora-A protein expression in tumor tissue represent a risk group with poor disease-free and overall survival (EGFRlow Aurora-Alow versus EGFRhigh Aurora-Ahigh, p = 0.024). Treating SCCHN cell lines with a pan-Aurora kinase inhibitor resulted in defective cytokinesis, polyploidy and apoptosis, which was effective irrespective of the EGFR status. Combined Aurora kinase and EGFR targeting using a monoclonal anti-EGFR antibody was more effective compared to single EGFR and Aurora kinase inhibition. Comparing pan-Aurora kinase and Aurora-A targeting hints towards a strong and clinically relevant biological effect mediated via Aurora kinase B. Taken together, our findings characterize a new poor risk group in SCCHN patients defined by elevated EGFR and Aurora-A protein expression. Our results demonstrate that combined targeting of EGFR and Aurora kinases represents a therapeutic means to activate cell cycle checkpoints and apoptosis in SCCHN.

Calmodulin protects Aurora B on the midbody to regulate the fidelity of cytokinesis

“…49 Investigations of small molecule Aurora B therapeutics are currently on the way, as several Aurora B protein inhibitors are entering clinical trials. [54][55][56][57][58][59] However, all the research so far were all focused on the inhibition of Aurora B activity. When testing CaM inhibitors on human adenocarcinoma cell growth, only calmidazolium displayed highly potent inhibitory activity (K d = 46 nM, Fig.…”

Depletion of Aurora A leads to upregulation of FoxO1 to induce cell cycle arrest in hepatocellular carcinoma cells

“…Silencing or inhibiting Aurora A kinase is effective for inhibition of growth and apoptosis in various tumor types. 36,37 However, the detailed underlying mechanism of the growth which spans a 1.8-kb sequence upstream of the first ATG, was linked to a luciferase reporter gene. Co-transfection of this plasmid and the Aurora A shRNA resulted in an approximately 5-fold increase in luciferase activity (Fig.…”

The induction of polyploidy or apoptosis by the Aurora A kinase inhibitor MK8745 is p53-dependent

“…In a study using squamous cell cancer of the head and neck, overexpression of Aurora kinase A is associated with an additive antiproliferative effect upon combining pan Aurora inhibitor with EGFR 19 by inducing more polyploidy. Another study used Actinomycin D in normal fibroblasts with wildtype p53 to rescue cells from VX-680-induced polyploidy and cellular abnormalities.…”