   Example
of the Response to Gefitinib in a patient with refractory non-small-cell
lung cancer. A computed tomographic scan of the chest in patient 6 shows
a large mass in the right lung before treatment with gefitinib was begun
(Panel A) and marked improvement six weeks after gefitinib was initiated
(Panel B). |
|
|
Raffaella Sordella Assistant Professor Ph.D., University of Turin, 1998 Molecular therapeutics; signal transduction email sordella@cshl.edu, phone (516) 367-5052, fax (516) 367-8454
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. |
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.