, 2011, Accepted: August 22, 2011, Published: August 23, 2011 Copyright: © Hoellein et al. This is an open access article distributed under the terms JNJ-7706621 CDK inhibitor of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract: Squamous cell cancer of the head and neck 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 and Aurora kinase 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 . BMS-554417 468741-42-6 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. Introduction Squamous cell cancer of the head and neck is the sixth leading cause for cancer deaths worldwide . Despite recent progress in understanding SCCHN biology and improved treatment, the 5 year survival has remained 50 percent for the past two decades. 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 . Several genetic alterations have been described in SCCHN, including mutations in the p53 tumor suppressor gene and mutations in genes that encode cell cycle proteins such as p16 and cyclin D1.
In addition, several oncogenic pathways including Ras, PI3K/PTEN/Akt, TGF β/BMP and EGFR/STAT3 are up regulated in SCCHN . Epidermal growth factor receptor overexpression in SCCHN is often caused by gene amplification , and elevated expression correlates with poor disease control and metastasis . Furthermore, overexpression of two of its ligands, EGF and transforming growth factoralpha , has been linked to a poor prognosis . 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 . The impactjournals/oncotarget 600 Oncotarget 2011, 2: 599 609 addition of the monoclonal antibody C225 to the standard first line regimen cisplatin/5 fluorouracil not only increased the rate of objective responses but also improved progression free and overall survival in patients with recurrent or metastatic SCCHN .
The Aurora kinases A and B are highly conserved serine/threonine kinases that play essential and distinct roles in mitosis . Specifically, Aurora A is required for the assembly of the mitotic spindle, where it accumulates on centrosomes at the spindle poles during prophase until metaphase. Recently a kinase independent role in mitotic spindle assembly has been reported for Aurora A . Aurora B is required for mitotic progression and cytokinesis, and is localized, along with inner centromeric protein and survivin, at centromeres and the spindle midzone during the metaphase to anaphase transition . AURORA A mRNA is amplified in a variety of human ca