Why Cancer 'Takes a Lickin' and Keeps on Tickin'

Melanoma drug resistance tied to healthy cells

(RxWiki News) So how does cancer outsmart drugs to keep on growing? Researchers are finding some answers in most unlikely places.

Inside a tumor, healthy cells live alongside cancer cells. New research suggests that it could be these healthy cells that are helping the cancer cells to keep on tickin'.

"Research combination cancer therapies."

A team of researchers from the Broad Institute, Dana-Farber Cancer Institute, and Massachusetts General Hospital uncovered these secrets after studying how healthy and diseased cells interact inside a tumor - what scientists call the tumor microenvironment.

"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, director of the Broad's Cancer Program and Charles A. Dana Investigator in Human Cancer Genetics at the Dana-Farber Cancer 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," said Dr. Golub, who is also a professor at Harvard Medical School and an investigator at the Howard Hughes Medical Institute

To explore this, researchers grew cancer cells and healthy cells in a test tube and added anti-cancer therapies to see how they reacted.

Cancer cells that were grown alone died in the presence of the drugs. However, when the two types of cells were cultured together, the cancer cells became resistant to more than half of the 23 agents they were exposed to.

This is the response that clinicians see with such cancers as melanoma, the most serious form of skin cancer.

Targeted therapies attack a common mutation found in the gene called BRAF that's seen in many melanomas. Some patients respond well to the BRAF blockers, and the tumors seem to disappear, while other patients see only a slight shrinking of the tumor.

The researchers said this mixed response suggests that some tumors have what they call "innate resistance" - that is, they evade the drugs from the get go.

"Even though recent advances in targeted therapy have caused tremendous excitement in melanoma, the fact remains that drug resistance eventually develops in nearly all metastatic melanomas treated with RAF inhibitors and, in some cases, is present at the outset of treatment," said Levi A. Garraway, MD, PhD, a senior associate member of the Broad Institute and associate professor at the Dana-Farber Cancer Institute and Harvard Medical School.

To delve deeper, the investigators measured hundreds of substances that normal cells secrete. The one linked to BRAF inhibitor resistance is called hepatocyte growth factor (HGF), which interacts with another factor - the MET receptor - that's tied to tumor growth.

To repeat these findings, the researchers worked with 34 patient tumor samples. Tumor response was linked to the levels of HGF present.

Several drugs that block HGF/MET are either in development or are approved to treat other conditions. So testing these agents combined with BRAF inhibitors can take place in future clinical trials.

"Drug resistance should no longer surprise us," said Dr. Golub. "We're thinking about how to do this – how to systematically dissect resistance – much earlier in the drug development process so that by the time a new drug enters the clinic, we have a good sense of what the likely mechanisms of resistance will be and have a strategy to combat them." 

No funding information or financial disclosures were provided.

Review Date: 
July 6, 2012