Molecular mechanisms of oncogenesis and mouse models of cancer
The Varmus Laboratory uses a variety of experimental approaches to understand the molecular mechanisms of oncogenesis.
(i) In current work on mouse models, the central questions concern the functions required to maintain the oncogenic state; the relationship between normal development lineages and oncogenic events that disturb development; the molecular basis of tumor progression; and strategies for targeted therapeutics. These issues are being addressed through the development and study of models for cancers of the breast, pancreas, lung, mesenchymal tissues, and plasma cells, using methods that include conventional and regulated transgenes, non-conditional and conditional null mutations, and tissue specific delivery of genes and inhibitory RNA's with avian retroviral vectors.
(ii) Our studies of lung cancer were triggered by dramatic remissions induced in a minority of lung cancers that have characteristic mutations in the EGF receptor gene when treated with certain tyrosine kinase inhibitors. We continue to look for additional oncogenic mutations in collaboration with the NIH's Cancer Genome Atlas project, have recapitulated EGFR-induced cancers (and K-Ras-induced cancers) in mouse models, and are seeking ways to improve therapy and avoid the secondary drug resistance that we have recently identified as a consequence of a second mutation in the EGFR tyrosine kinase domain. In addition, we are using high throughput methods with small molecules and inhibitory RNAs to identify additional potential targets for therapy and using mass spectroscopy and other proteomics methods to look for proteins involved in oncogenic signaling pathways in EGFR- and K-Ras-driven lung tumor cells.
Recent representative publications:
1. Varmus, H., Pao, W., Politi, K., Podsypanina, K., Du, Y.-C.N. Oncogenes Come of Age. CSHSQB 70:1-9, 2005.
2. Pao, W., Miller, V.A., Politi, K., Riely, G.J., Somwar, R., Zakowski. M.F., Kris, M.G., Varmus, H.E. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2:3 e73, 2005.
3. Politi, K., Zakowski, M.F., Fan, P., Schonfeld, E.A. Pao, W. and Varmus, H.E. Lung adenocarcinomas induced in mice by mutant EGF receptors found in human lung cancers respond to a tyrosine kinase inhibitor or to down-regulation of the receptors. Genes Dev. 20:1496-1510, 2006.
4. Du, Y-C.N., Lewis, B.C., Hanahan, D., and Varmus, H.E. Assessing Tumor Progression Factors by Somatic Gene Transfer in a Mouse Model: Bcl-xL Promotes Islet Tumor Cell Invasion. PLoS Biology 5: e276, 2007.
5. K. Podsypanina, K.A. Politi, L.J. Beverly and H. E. Varmus. Oncogene cooperation in tumor maintenance and tumor recurrence in mouse mammary tumors induced by Myc and mutant Kras. PNAS:105 5242-5247 (2008).
