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Associate Professor
Ph.D., University of Turin, 1998

Molecular therapeutics; signal transduction

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Raffaella Sordella Cancer is a genetic disease characterized by the progressive accumulation of mutations and epigenetic changes. As a consequence, cells sense and respond differently to environmental cues, grow abnormally, and fail to undergo apoptosis and senescence. Surprisingly, despite their large variety of genetic abnormalities, cancer cells are incredibly sensitive to the reversal of certain mutations. A few years ago Bernard Weinstein described this phenomenon as "oncogene addiction". Examples are provided by c-myc, K-Ras, H-Ras, Bcr-Abl, Her-2, Wnt1.

Understanding why cancer cells are dependent on specific oncogenes could lead to the development of more effective therapies. Recently, we identified new epidermal growth factor receptor (EGFR) somatic mutations in non-small cell lung cancer patients that respond dramatically to treatment with Iressa, a selective inhibitor of EGFR. In particular we demonstrated that the presence of these mutations render the cells "addicted" to signaling activated by the mutant EGFR alleles. In my group we will use mutant EGFR as a paradigm to understand aspects of "oncogene addiction". Specifically, we will use state-of-the-art proteomic and genomic techniques to identify the molecular mechanism behind EGFR dependency.

Using similar methodologies we are also interested in uncovering molecular determinants of resistance to EGFR selective inhibitors. Finally, we intend to perform functional genomic screens to discover novel genetic lesions to which cancer cells become addicted.

Selected Publications

Smolen, G.A., Sordella, R., Muir, B., Mohapatra, G., Barmettler, A., Archibald, H., Kim, W.J., Okimoto, R.A., Bell, D.W., Sgroi, D.C., Christensen, J.G., Settleman, J., Haber, D.A. 2006. Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor. Proc Natl Acad Sci USA 103: 2316–2321.

Haber, D.A., Bell, D.W., Sordella, R., Kwak, E.L., Godin-Heymann, N., Sharma, S.V., Lynch, T.J., Settleman, J. 2005. Molecular targeted therapy of lung cancer: EGFR mutations and response to EGFR inhibitors. Cold Spring Harb Symp Quant Biol. 70:419–4426.

Kwak, E.L.*, Sordella, R.*, Bell, D.W.*, Godin-Heymann, N.*, Okimoto, R.A., Brannigan, B.W., Harris, P.L., Driscoll, D.R., Fidias, P., Lynch, T.J., Rabindran, S.K., McGinnis, J.P., Wissner, A., Sharma, S.V., Isselbacher, K.J., Settleman, J., Haber, D.A. 2005. Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc Natl Acad Sci USA 102: 7665–7670.

Sordella, R., Bell, D.W., Haber, D.A., Settleman, J. 2004. Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 305: 1163–1167.

Lynch, T.J.*, Bell, D.W.*, Sordella, R.*, Gurubhagavatula, S., Okimoto, R.A., Brannigan, B.W., Harris, P.L., Haserlat, S.M., Supko, J.G., Haluska, F.G., Louis, D.N., Christiani, D.C., Settleman, J., Haber, D.A. 2004. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 350: 2129–2139.