Molecular Mechanisms of Aurora Kinase A Dysfunction in Lung Cancer

Junior Investigator and Project Leader

Scott A. Gerber, Ph.D.
Associate Professor of Genetics
Geisel School of Medicine at Dartmouth
603.653.3679
www.dartmouth.edu/~genetics/faculty/gerber
www.cancer.dartmouth.edu/members/Gerber
http://proteomics.dartmouth.edu

Lung malignancies are the leading causes of cancer deaths worldwide. An estimated 160,000 Americans and 1.2 million people around the world will die from lung cancer in 2007. Based on status quo detection strategies and therapies, only 16% of patients diagnosed this year with lung cancer will survive for five years.

Aurora kinase A is frequently (53 – 69%) found at high expression levels in human lung cancers. The chromosomal locus (20q13) at which Aurora A resides is frequently amplified in cancer, and post-translational mechanisms have been shown to stabilize and enhance Aurora A expression in the absence of gene amplification. Simply overexpressing the kinase can transform normal fibroblasts, classifying Aurora A as a bona fide oncogene. Importantly, cells transformed with a constitutively active form of the kinase induce a more malignant tumor phenotype in mouse xenograft models of cancer. Furthermore, overexpression of Aurora A leads to polyploidization, centrosome amplification, and chromosomal instability, features that play important roles in the establishment and potential maintenance of cancers. Of particular clinical relevance, cells that overexpress Aurora A exhibit substantial resistance to Taxol-induced apoptosis. At present, clinical trials for inhibitors of Aurora kinase activity are underway to determine their efficacy in selectively killing cancer cells.

Aurora kinase A functions from early- to mid-mitosis by recruitment and activation of centrosome- and mitotic spindle-associated factors essential for proper orientation of spindle poles and microtubule dynamics. Properly regulated Aurora A localization and activity is required for multiple functions in mitosis, including the spindle assembly checkpoint, chromosome segregation, and cytokinesis. However, surprisingly little is known about the actual molecular targets of Aurora A activity, even within the normal activation state and function of the kinase. Select substrates have been identified by indirect means (siRNA) and these substrates are primarily associated with centrosome function, including the kinesin Eg5 and the acidic coiled-coil protein TACC.

We hypothesize that targets of dysregulated Aurora kinase A activity are involved in the mechanism by which cells that overexpress Aurora A become aneuploid and cancerous. We assert that in order to understand this mechanism, we must first comprehensively determine which molecules lie downstream of dysregulated Aurora kinase A activity. Using highly integrated, modern proteomics methods, our lab seeks to understand the process of Aurora kinase A-mediated transformation in lung cancer by systematically mapping and studying the substrate networks of proteins that are targeted by this oncogenic kinase.

Students

Arminja N. Kettenbach, Ph.D., Postdoctoral Fellow
Arminja's research is focused on developing kinomics approaches to study mitotic kinase signaling in lung cancer.

Brendan K. Faherty, Student
Brendan's research involves developing high throughput algorithms for translational mass spectrometry data analysis.

Devin K. Schweppe, Student
Devin's research is directed towards the roles of Aurora A in non-mitotic functions in lung cancer cells.

Jason M. Gilmore, Student
Jason's research involves analytical and statistical approaches to understanding and correcting bias in large-scale phosphoproteomics experiments.

Publications

Pubmed