Raffaella Sordella

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.