Ph.D., University of Turin, 1998
Two challenges in cancer biology guide my work: first, how do tumors become addicted to certain gene products, and second, how do tumors develop resistance to anti-cancer drugs. I focus on the epidermal growth factor receptor (EGFR), which is both addictive when mutated and a common source of drug resistance. We are also identifying new targets for the treatment of lung cancer.
Despite their large variety of genetic abnormalities, cancer cells have been found to be extremely sensitive to the reversal of certain mutations. Raffaella Sordella and colleagues study why cells in certain cancers are responsive to the inhibition of one particular gene or gene product. Why, for instance, do non-small-cell lung cancer (NSCLC) cells that have a particular mutation in the epidermal growth factor receptor (EGFR) respond dramatically to its inhibition by the drug Tarceva? This occurs in 15%–20% of patients, the great majority of whom, within 1–3 years, develop resistance. Various mutations have been implicated in about half of resistant patients. Sordella and colleagues have discovered a new resistance mechanism in a subpopulation of NSCLC cells that are intrinsically resistant to Tarceva. These tumor cells were observed to secrete elevated amounts of a growth factor called transforming growth factor-β (TGF-β), which in turn increases secretion of interleukin-6 (IL-6), an immune signaling molecule. Significantly, these effects were independent of the EGFR pathway. The team therefore hypothesizes that inflammation is one of the factors that can render a tumor cell resistant to treatment with Tarceva. In other work, Sordella collaborates with the Krainer lab to study whether alternative splicing has a role in the failure of p53-mediated senescence to halt oncogenesis in certain lung cancers.
Smolen, G. A. and Sordella, R. and Muir, B. and Mohapatra, G. and Barmettler, A. and Archibald, H. and Kim, W. J. and Okimoto, R. A. and Bell, D. W. and Sgroi, D. C. and Christensen, J. G. and Settleman, J. and Haber, D. A. (2006) Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752. Proceedings of the National Academy of Sciences of the United States of America 103(7) pp. 2316-21.
Kwak, E. L. and Sordella, R. and Bell, D. W. and Godin-Heymann, N. and Okimoto, R. A. and Brannigan, B. W. and Harris, P. L. and Driscoll, D. R. and Fidias, P. and Lynch, T. J. and Rabindran, S. K. and McGinnis, J. P. and Wissner, A. and Sharma, S. V. and Isselbacher, K. J. and Settleman, J. and Haber, D. A. (2005) Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proceedings of the National Academy of Sciences of the United States of America 102(21) pp. 7665-70.
Haber, D. A. and Bell, D. W. and Sordella, R. and Kwak, E. L. and Godin-Heymann, N. and Sharma, S. V. and Lynch, T. J. and Settleman, J. (2005) Molecular targeted therapy of lung cancer: EGFR mutations and response to EGFR inhibitors. Cold Spring Harbor Symposia on Quantitative Biology 70pp. 419-26.
Sordella, R. and Bell, D. W. and Haber, D. A. and Settleman, J. (2004) Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 305(5687) pp. 1163-7.
Lynch, T. J. and Bell, D. W. and Sordella, R. and Gurubhagavatula, S. and Okimoto, R. A. and Brannigan, B. W. and Harris, P. L. and Haserlat, S. M. and Supko, J. G. and Haluska, F. G. and Louis, D. N. and Christiani, D. C. and Settleman, J. and Haber, D. A. (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. The New England Journal of Medicine 350(21) pp. 2129-39.Additional materials of the author at
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