Research News
Cell-to-Cell "Conversation" Leads to Drug Resistance in Lung Cancers
One of the most vexing problems in treating cancer is the propensity of tumors to develop resistance to a wide range of anticancer drugs, including the new generation of treatments designed to target specific cancer-related mutations. Now, a team of researchers in Japan has shown that cells other than those in the tumor can play a key role in the development of drug resistance.
Seiji Yano, Ph.D., headed a team of researchers from Kanazawa University that explored the role that fibroblast cells play in the development of resistance in lung cancer cells that have mutations that activate the epidermal growth factor receptor (EGFR). This receptor is overexpressed in the majority of non-small cell lung cancers and it is the target of two of the drugs, gefitinib (Iressa) and erlotinib (Tarceva), approved to treat lung cancer. Several clinical trials have demonstrated that up to 75% of patients who have this mutation respond positively to these drugs, but clinical experience has also shown that some 25% of patients develop resistance to these drugs.
The investigators, who published the results of their studies in the journal Clinical Cancer Research, tested the hypothesis that fibroblast cells, which normally synthesize the extracellular matrix that holds cells and tissues in place, are somehow involved in the development of resistance. They based this hypothesis on the finding that lung cancer cells with EGFR-activating mutations recruit human fibroblasts, particularly when the tumor cells were exposed to one of the two anti-EGFR therapies.
When the researchers grew lung cancer cells with EGFR-activating mutations in the presence of fibroblasts, the tumor cells spontaneously developed resistance to the anti-EGFR therapies. The investigators identified the culprit as a small protein known as hepatocyte growth factor, and when the researchers examined anti-EGFR resistant tumors in humans they found fibroblasts at the periphery of the tumors that were producing large amounts of this growth factor.
In a final set of experiments, Yano and his colleagues implanted tumor cells and fibroblasts into mice and then treated them with a combination of gefitinib and either an antibody that binds to hepatocyte growth factor or a small molecule known to block the biological activity of this growth factor. Control animals did not receive the antibody or small molecule. Compared to the control animals, the treated animals did not develop any resistance to anti-EGFR therapy. Based on these results, the researchers suggest that new strategies targeting the crosstalk between tumors and cells in their microenvironment could circumvent the life-threatening development of drug resistance in tumors.
The details of this study appear in a paper titled, “Crosstalk to Stromal Fibroblasts Induces Resistance of Lung Cancer to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors.” An abstract of this paper is available at the journal’s Web site.
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