Jeffrey Settleman

Department of Medicine
Massachusetts General Hospital, Cancer Center
Building 149, 13th Street
Charlestown, MA 02129
Tel: (617) 724-9556
Fax: (617) 726-7808
Email: Settleman@helix.mgh.harvard.edu
10 postdoctoral fellows

Our laboratory is investigating the regulation and biological function of signal transduction pathways in the context of human cancer. We are particularly interested in the role of protein kinase-mediated signaling pathways in human tumorigenesis. There are more than 500 kinases encoded by the human genome and many of these have been implicated in cancer. We are exploring mechanisms of molecularly-targeted cancer therapeutics that influence kinase-mediated signaling pathways that become dysregulated during human tumorigenesis. These efforts have led to the establishment of a link between a novel class of activating EGF receptor mutations in lung cancer and the response to EGF receptor inhibitor drugs in a subset of treated patients. . To begin to identify additional genetic determinants of drug response in human cancers, we have established a large collection of human cancer cell lines (>1000) that we are testing for sensitivity to targeted kinase inhibitors. We have established a high-throughput fully automated screening platform to test these lines for drug sensitivity and to identify biomarkers that can be used clinically to guide treatment. These studies are expected to provide further insights into the “wiring” of a tumor cell, and could lead to the optimization of molecularly targeted therapies.

We are also conducting studies to develop a better understanding of the “Oncogene addiction” phenomenon. Oncogene addiction refers to the acquired dependency of cancer cells on a single cellular pathway for survival or sustained proliferation, despite the fact that such cells have accumulated numerous genetic alterations. Moreover, oncogene addiction may account for the dramatic clinical responses reported in some cancer patients treated with the various targeted kinase inhibitors. However, a molecular mechanism to explain oncogene addiction has been elusive. We have conducted studies that reveal a potential mechanism to explain oncogene addiction that involves a shift in the balance of pro-survival and pro-apoptotic signals in oncogene-dependent cancer cells. We are continuing to pursue the specific nature of signaling pathways that contribute to this phenomenon, which may have important implications for the therapeutic use of targeted kinase inhibitors.

Finally, we are interested in understanding the mechanisms by which cancer cells become resistant to targeted drugs that disrupt signaling pathways. We have developed several in vitro models of drug resistance and we are examining the relationship between cancer stem cells and drug resistance.

References:

• Sharma, S.V., Settleman, J. Oncogene addiction: setting the stage for molecularly targeted cancer therapy. Genes Dev. 2007, 21:3214-31.
• McDermott, U., Sharma, S.V., Dowell, L., Greninger, P., Montagut, C., Lamb, J., Archibald, H., Raudales, R., Tam, A., Lee, D., Rothenberg, S.M., Supko, J., Sordella, R., Ulkus, L.E., Iafrate, A.J., Maheswaran, S., Njauw, C.-N., Tsao, H., Drew, L., Hanke, J.H., Ma, X.-J., Erlander, M.G., Gray, N., Haber, D.A., Settleman, J. Identification of genotype-correlated sensitivity to selective kinase inhibitors using high-throughput tumor cell line profiling. Proc Natl Acad Sci USA 2007 104:19936-41.
• Quinlan, M.P. Quatela, S.E., Philips, M.R., Settleman, J. Activated Kras, but not Hras or Nras, may initiate tumors of endodermal origin via stem cell expansion. Mol Cell Biol. 2008 28:2659-74.
• Singh, A., Greninger, P., Rhodes, D., Koopman, L., Violette, S., Bardeesy, N., Settleman, J. A gene expression signature associated with ³K-Ras addiction² reveals regulators of EMT and tumor cell survival. Cancer Cell
  2009 15:489-500.