Tumor microenvironment helps skin cancer cells resist drug treatment

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Neighboring non-cancer cells may contribute to drug resistance

One of cancer's most frightening characteristics is its ability to return after treatment. In the case of many forms of cancer, including the skin cancer known as melanoma, tailored drugs can eradicate cancer cells in the lab, but often produce only partial, temporary responses in patients. One of the burning questions in the field of cancer research has been and remains: how does cancer evade drug treatment?

New research by a team from Dana-Farber Cancer Institute, the Broad Institute and Massachusetts General Hospital suggests that some of the answers to this question do not lie in cancer cells themselves. To find the answers, scientists are looking beyond tumor cells, studying the interplay between cancer cells and their healthy counterparts. The research team has found that normal cells that reside within the tumor, part of the tumor microenvironment, may supply factors that help cancer cells grow and survive despite the presence of anti-cancer drugs. These findings appear online this week in a paper published in Nature.

"Historically, researchers would go to great lengths to pluck out tumor cells from a sample and discard the rest of the tissue," said senior author Todd Golub, MD, the Charles A. Dana Investigator in Human Cancer Genetics at Dana-Farber Cancer Institute, pediatric oncologist at Dana-Farber/Children's Hospital Cancer Center, and director of the Broad's Cancer Program. Golub is also a professor at Harvard Medical School and an investigator at Howard Hughes Medical Institute. "But what we're finding now is that those non-tumor cells that make up the microenvironment may be an important source of drug resistance."

To investigate how the tumor microenvironment may contribute to drug resistance, the researchers designed experiments in which cancer cells were grown in the same wells (miniscule test tubes no larger than a pencil eraser) along with normal cells. These co-cultured cells were then treated with anti-cancer drugs. When grown alone, such cancer cells died in the presence of many of these targeted agents, but when grown together with normal cells, cancer cells developed resistance to more than half of the 23 agents tested.

These observations reflect what clinicians often see in patients with cancers such as melanoma. In the case of melanoma, targeted therapies have been developed against a specific, common mutation in a gene known as BRAF. While some patients' tumors show an overwhelming response to BRAF inhibitors and seem to disappear, other patients' tumors only respond by slightly decreasing in size. The failure to shrink tumors at the outset suggests that those tumors possess some level of innate resistance — the ability to evade drugs from the beginning of treatment.


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