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 (EGFR(low)Aurora-A(low) versus EGFR(high)Aurora-A(high), 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.
Highlights
Squamous cell cancer of the head and neck (SCCHN) is the sixth leading cause for cancer deaths worldwide [1]
AURORA-A transcripts were expressed at significantly higher levels in SCCHN tumor samples as compared to normal control tissue (p=0.002, Figure 1), and the median relative expression in surviving patients was lower as compared to patients dying from SCCHN (n.s.)
While protein levels of Epidermal growth factor receptor (EGFR) (Figure 3A) or Aurora-A (Figure 3B) above median assessed by IHC in a Kaplan Meier analysis did not identify a population with a significantly reduced disease-free survival (EGFR: p=0.10; Aurora-A; p=0.21), our analysis identifies a poor risk population with regard to overall and disease-free survival that is characterized by above median levels of EGFR (EGFRhigh) and Aurora-A (Aurora-Ahigh) (p=0.024, compared to EGFRlow and Aurora-Alow, Figure 2C)
Summary
Squamous cell cancer of the head and neck (SCCHN) is the sixth leading cause for cancer deaths worldwide [1]. There is a pressing need to improve therapy in particular for patients with metastatic disease or local recurrence, where the median progression-free and overall survival is only ~ 6 months and ~11 months, respectively [2,3,4]. Several oncogenic pathways including Ras, PI3K/PTEN/Akt, TGF-β/BMP and EGFR/STAT3 are up-regulated in SCCHN [4,5,6,7,8,9,10,11]. Epidermal growth factor receptor (EGFR) overexpression in SCCHN is often caused by gene amplification [12], and elevated expression correlates with poor disease control and metastasis [13,14]. The major signaling pathways activated by EGFR are the RAS-RAF-MAP kinase pathway, which is mainly involved in proliferation, and the PI3K-PTEN-AKT pathway, which is mainly involved in survival [16].
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