Laurel Schwartz Professor of Medicine
Harvard Medical School
Center for Molecular Therapeutics
Massachusetts General Hospital Cancer Center
Research Summary Our laboratory is investigating the regulation and biological function of signal transduction pathways in the context of human cancer as they relate to therapeutic opportunities. 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, for example, to the establishment of a link between a class of somatic 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 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 providing further insights into the “wiring” of a tumor cell and the relationship between cancer cell genotypes and drug sensitivity, and could therefore 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, which remains an important limitation to their clinical utility. We have developed several in vitro models of drug resistance and we are examining the relationship between a newly identified sub-population of cancer cells that we describe as “drug tolerant” and the more stable forms of genetically-mediated drug resistance.
Jeffrey Settleman, PhD
Group MembersAssistant Professor
Lab ManagerAdministrative Assistant
There are no available research positions at this time.
Sharma, S.V., Settleman, J. Oncogene addiction: setting the stage for molecularly targeted cancer therapy. Genes Dev. 2007, 21:3214-31.
McDermott, U., Iafrate, A.J., Gray, N.S., Shioda, T., Classon, M., Maheswaran, S., Zhou, W., Choi, H.G., Dowell, L., Ulkus, L.E., Kuhlmann, G., Greninger, P., Christensen, J.G., Haber, D.A., Settleman, J. Genomic alterations of anaplastic lymphoma kinase (ALK) may sensitize tumors to ALK inhibitors. Cancer Res. 2008, 68(9):3389-95.
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(8):2659-74.
Montagut, C., Sharma, S.V., Shioda, T., McDermott, U., Ulman, M., Ulkus, L.E., Dias-Santagata, D., Stubbs, H., Lee, D.Y., Singh, A., Drew, L., Haber, D.A., Settleman, J. Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma. Cancer Res. 2008 68:4853-4861.
Jiang, W., Betson, M, Mulloy, R., Foster, R., Lévay, M., Ligeti, Settleman, J. p190A RhoGAP is a glycogen synthase kinase-3b substrate required for polarized cell migration. J. Biol. Chem. 2008: 283(30):20978-88.
Rothenberg, S.M., Engelman, J., Le, S. Riese, D.J., II, Haber, D.A., Settleman, J. Modeling oncogene addiction with RNA interference. Proc. Natl. Acad. Sci. USA, 2008: 105(34):12480-4
McDermott, U., Ames, R.Y., Iafrate, A.J., Maheswaran, S., Stubbs, H., Greninger, P., McCutcheon, K., Milano, R., Tam. A., Lee, DY., Lucien, L., Brannigan, B.W., Ulkus, L.E., Ma, X.J., Erlander, M.G., Haber, D.A., Sharma, S.V., Settleman, J. Ligand-dependent PDGF receptor-alpha activation sensitizes rare lung cancer and sarcoma ce¬lls to PDGF receptor kinase inhibitors Cancer Res. 2009; 69:3937-3946.
Singh, A., Greninger, P., Rhodes, D., Koopman, L., Violette, S., Bardeesy, N., Settleman, J. A gene expression signature associated with “K-Ras addiction” reveals regulators of EMT and tumor cell survival. Cancer Cell 2009 15:489-500.