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Author's Affiliation: Division of Clinical Translational Research, Translational Genomics Research Institute, Phoenix, Arizona
Requests for reprints: Daniel D. Von Hoff, Division of Clinical Translational Research, Translational Genomics Research Institute, 445 N. 5th St., Phoenix, AZ 85004. Phone: 1-602-343-8492; Fax: 1-602-343-8484; E-mail: dvh{at}tgen.org.
The retrospective study by Reiter et al. in this issue of Clinical Cancer Research (1) provides further support to the growing body of evidence that Aurora A kinase is an important player in cancer. It also identifies a potential new prognostic marker and drug target for head and neck squamous cell carcinoma (HNSCC), a disease that is in urgent need of biomarkers for early diagnosis and molecular targets for therapeutic development.
HNSCC is the malignancy of the upper aerodigestive tract, which generally includes cancers of oral cavity, salivary gland, nasal cavity, pharynx, and larynx. It is the sixth most common cancer with about 55,000 and 500,000 new cases every year in the United States and worldwide, respectively. Despite advances in surgical and other treatments, HNSCC is still a devastating disease as the survival rates of this disease virtually have not changed for the past 30 years. Like many other solid tumors, HNSCC harbors complex molecular abnormalities. To date, several genetic alterations with prognostic potential have been identified (2, 3). For example, both p53 and p16 are inactivated in the majority of HNSCC (52-82%, p16; 50-69%, p53; ref. 2). Cyclin D1, cyclooxygenase-2, epidermal growth factor receptor, vascular endothelial growth factor, and matrix metalloproteinases have also been shown to be overexpressed and/or amplified in HNSCC. The study by Reiter et al. describes yet another potential prognosis marker for HNSCC, the Aurora A kinase.
Aurora A (also known as AURKA, Aurora-2, AIK, BTAK, and STK15) belongs to a family of mitotic serine/threonine kinases, which include two other members, Aurora B and Aurora C, in the human genome. The Aurora A and Aurora B kinases are known to play important yet distinct roles in mitosis (4, 5). The Aurora A kinase is involved in centrosome maturation and separation and consequently regulates spindle assembly and stability. The Aurora B kinase (also known as AURKB, Aurora-1, AIK2, and STK12), on the other hand, is a chromosome passenger protein and regulates chromosome segregation and cytokinesis. The cellular function of Aurora C is less clear, although there is evidence to suggest that it might also be a chromosomal passenger protein (6). Maintaining a proper level of Aurora kinase expression and activity is critical to the normal chromosome ploidy. It has been shown that up-regulation of Aurora A kinase can result in polyploidy (7). Increase in Aurora A protein level induces centrosome amplification and spindle abnormality, which in turn triggers p53-dependent G1 checkpoint arrest. In cells with wild-type p53, increased Aurora A kinase activity can inactivate p53 and help the cells escape the G1 checkpoint arrest to eventually become polyploidy. In cells with a defective p53, G1 checkpoint arrest is not induced. Instead, cells enter the S phase after a prolonged mitosis and continue to divide with uneven separation of the centrosomes and chromosomes. Because chromosomal instabilities, such as aneuploidy, are a hallmark of human cancer, one might expect that Aurora A kinase plays a role in tumorigenesis and tumor progression. In fact, since its identification in the late 1990s (8, 9), the human Aurora A kinase gene has been reported to be overexpressed and/or amplified in a variety of cancer types, including breast, prostate, pancreas, bladder, esophagus, ovarian, endometrial, gastric, glioma, medulloblastoma, non–Hodgkin's lymphoma, and mantle cell lymphoma (4, 10–12). Many of the studies linked the deregulation of Aurora A to higher tumor stages and poor prognosis of the patients. The HNSCC reported by Reiter et al. is the latest addition to this growing list of cancers with dysregulations in Aurora A.
Reiter et al. describe in their study for the first time the significant correlation between Aurora A overexpression and poor prognosis in HNSCC. After examining the Aurora A mRNA level in 66 patient samples, they found that Aurora A mRNA overexpression was strongly correlated with tumor and nodal classification, tumor stage, and distant metastasis (P < 0.0001). Immunohistochemical staining of Aurora A protein in a subset (34) of the patient samples confirmed this correlation at the protein level, albeit at relatively moderate statistical significance (P = 0.0183, regional lymph node metastasis; P = 0.03, distant metastasis). More importantly, the authors further showed that elevated Aurora A mRNA level was significantly correlated with shortened disease-free survival (P = 0.03) and overall survival (P < 0.01). The authors also observed increased centrosome abnormalities in cells with high Aurora A mRNA level. Interestingly, they did not find a strong correlation between Aurora A expression and chromosomal aneusomy.
The findings by Reiter et al. not only suggest that Aurora A is a potential new biomarker for HNSCC but also open the possibility of therapeutic targeting of Aurora A in HNSCC. Aurora kinases as drug targets have been intensely pursued by several academic and industrial groups (13, 14). At least four Aurora kinase inhibitors (VX-680, AZ1152, MLN8054, and AT9283) are currently in phase I clinical development. A phase II study in patients with advanced colorectal cancer was just initiated recently for VX-680 (http://www.vpharm.com/Productpipeline.html). It would be interesting to see whether any of these agents will show antitumor activity in patients with HNSCC.
There are several questions that remain unanswered with regard to the role of Aurora A in HNSCC. First, what is the mechanism of Aurora A overexpression in HNSCC? In general, multiple factors could contribute to protein overexpression: transcription activation by upstream regulators, increased protein stability, and gene amplification. However, for mitotic proteins, such as Aurora A, it could be only a simple reflection of increase in percentage of cells in G2-M phase of the cell cycle. If it is the latter, the significance of Aurora A overexpression in HNSCC might be reduced. Clinical experience with trastuzumab in breast cancer has taught us that the mechanism by which tumor cells gain overexpression of a target could have profound effect on patients' response to the therapy specific to the target. Therefore, understanding the mechanism of Aurora A overexpression is potentially critical to the success of Aurora A–targeted therapy. Second, is the Aurora A gene amplified in HNSCC cells? If it is, does the amplification correlate with late disease stage and poor prognosis in patients with HNSCC? DNA gains at chromosome 20q have been reported in HNSCC (15, 16). Because Aurora A gene is localized to 20q13.2, it is conceivable that Aurora A might be amplified in HNSCC. Indeed, Tatsuka et al. (17) reported that of the 11 oral squamous carcinoma samples examined, 4 had amplification in the Aurora A gene. Further study is needed to find out how common this amplification is in HNSCC. Third, what is the role of Aurora A kinase activity in HNSCC? It has been shown that the kinase activity is required for Aurora A to transform cells or induce metastasis (18). However, it is not clear whether high-level kinase activity is required for cancer cell survival. The underlining premise for Aurora kinase inhibitor–based therapy is that cancer cells with overexpressed/amplified Aurora A become addictive to high level Aurora kinase activity and/or become resistant to chemotherapeutics; therefore, elevated Aurora A activity is essential for their survival. From the preclinical data of Aurora kinase inhibitors reported thus far, this hypothesis seems to be holding its own. However, there is now evidence to show that a high level of Aurora A kinase might not be essential once the cancer is established (19). Finally, does p53 mutation correlate with Aurora A overexpression in HNSCC? As mentioned above, Aurora A kinase phosphorylates p53 and leads to its degradation, so cells can escape G1 checkpoint arrest induced by abnormal spindle assembly. On the other hand, such kinase activity is dispensable in cells without functional p53. Because p53 is frequently inactivated in HNSCC, it would be interesting to see if the combination of p53 mutation and Aurora A overexpression confers any additional prognostic value over either one alone.
A prospective clinical trial to test the strength of Aurora A kinase as a prognostic factor in HNSCC would be nice to have. However, with their careful work, Reiter et al. have given the field an excellent boost.
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Received 6/ 1/06; accepted 6/23/06.
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