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New mechanisms of tumor resistance to targeted therapy in lung cancer are discovered
Date:8/17/2010

hanism of resistance simply was not known."

Sordella's team, which was joined by investigators from Weill Cornell Medical College of Cornell University and the Boltzmann Institute for Cancer Research in Vienna, found what they regard as "compelling evidence" of other modes of resistance. One pertains to a population of NSCLC cells within untreated tumors that they found to be "intrinsically resistant" to Tarceva. These are cells--accounting for about 3% of the tumor samples studiedthat exhibit features suggestive of something scientists call EMT: the transition of normal epithelial cells to mesenchymal cells--cells with an increased metastatic potential.

This subpopulation of tumor cells were observed to secrete elevated amounts of TGF-β, a type of growth factor that plays a role in cell differentiation, development, and in regulation of the immune system. Up-regulation of TGF-β in these tumor cells resulted in increased secretion of a signaling molecule called IL-6, which among other things is also involved in immune responses. This subset of tumor cells with up-regulated TGF-β and increased IL-6 secretion was observed to resist treatment with Tarceva, independently of the EGFR pathway.

"This led us to the idea that inflammation might be one of the factors that could reduce a lung tumor cell's sensitivity to Tarceva," Sordella says. Since IL-6 and TGF-β are actively produced during the general inflammatory process, the team was led to explore whether inflammation mediated by non-cancer cells in the tumor microenvironment might also play a role in resistance to Tarceva. Using mouse models, the team was able to show precisely that.

Why IL-6 seems to be required for the survival of the cancer cells is not yet clear," Sordella notes. "We hypothesize that it plays a role in protecting cells from programmed cell-death, or apoptosis. We expect to investigate that possibility in future studies."


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Contact: Peter Tarr
tarr@cshl.edu
516-367-8455
Cold Spring Harbor Laboratory
Source:Eurekalert

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