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Tumors May Resist Cancer Drugs with Help from Neighboring Cells

Researchers have identified a protein secreted by nontumor cells that may help nearby tumors evade the effects of anticancer drugs. The results, published online in Nature on July 4, add to a body of evidence that interactions between cancer cells and surrounding cells in the tumor microenvironment may influence the growth of tumors and their responses to treatments.

Patients with cancer rarely have complete responses to targeted drugs, and this suggests that there are mechanisms that can render a substantial proportion of tumor cells innately resistant to therapies. Although genetic mutations that allow tumors to acquire resistance over time have been identified, less is known about sources of innate resistance.

To identify nontumor sources of innate resistance, Dr. Todd Golub of the Broad Institute and his colleagues grew cancer cells along with cells from the body's connective tissue, or stroma, in the lab. When they exposed these mixtures of stromal cells and cancer cells to targeted anticancer drugs, the cancer cells were resistant to 15 of the 23 agents evaluated.

An analysis of more than 500 factors secreted by noncancer cells indicated that a protein called hepatocyte growth factor (HGF) may make melanomas with BRAF gene mutations resistant to treatment with vemurafenib, a recently approved drug that targets BRAF-mutated melanoma cells.

When the authors tested 34 samples from patients with melanoma, they found a correlation between HGF levels and the amount of tumor shrinkage following vemurafenib treatment. They also found evidence of resistance mediated by the microenvironment in other cancers.

Several drugs that inhibit HGF or MET, the receptor on tumor cells for HGF, are in development or have been approved for other indications, the authors noted. Combination clinical trials in BRAF-mutant melanoma, colorectal cancer, and possibly other tumor types could be considered, they added.

"It is increasingly recognized that both the tumor and its microenvironment will need to be therapeutically targeted for maximum efficacy," commented Dr. Dinah Singer, director of NCI's Division of Cancer Biology. "This study provides an explicit example of a therapeutic strategy to address this."

Understanding the role of the tumor microenvironment in the initiation, progression, and spread of cancer, Dr. Singer added, is a goal of the Tumor Microenvironment Network, an initiative sponsored by NCI.

This research was supported in part by the National Institutes of Health (P50-CA093683 and U54-CA112962).