ddn Cancer Research News Exclusive: Leading the resistance
CAMBRIDGE, Mass.—There is no shortage of concern lately for the growing issue of drug-resistant bacteria, but there is another form of resistance in the pharmaceutical world that's causing just as much, if not more, of a problem: the tendency of cancer to resist and, consequently, return after treatment. In many forms of cancer, drug treatments and chemotherapy only produce partial or temporary responses in patients, and recent research from a team of researchers from the Broad Institute, the Dana-Farber Cancer Institute and Massachusetts General Hospital has shed some light on the biology of drug resistance in cancer. The article, "Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion," was published in the online edition of Nature July 4.
The research team has found that normal, healthy cells are present within tumors as part of the microenvironment, and seem to be responsible for supplying biological factors that help cancer cells to survive even in the face of anti-cancer drugs. Researchers examined tumors and their microenvironment by growing cancer cells in the same wells as normal cells, then exposing them to anti- cancer drugs. The cancer cells died when they were grown alone, but when they were grown together with normal cells, the cancerous cells were shown to develop resistance to more than half of the 23 anti-cancer drugs tested.
"We can take cancer cells out of a melanoma patient, put them on a dish, and most times they will turn out to be extremely sensitive to the targeted agents, but that's not what we see in patients," Ravid Straussman, a postdoctoral fellow at the Broad Institute and first author of the paper, said in a press release. "Why do we get just a partial response in most patients? We set out to dissect this question, and the next logical step was to think beyond cancer cells."
The team performed systematic, high-throughput screens of more than 40 cancer cell lines, and chose to focus on melanoma while they examined the idea that biological factors secreted by normal cells might help cancerous cells resist treatment.
"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," Levi A. Garraway, a senior associate member of the Broad Institute an associate professor at Dana-Farber Cancer Institute and Harvard Medical School, said in a press release.
One of the common mutations in melanoma is a mutation of the BRAF gene, and while some patients respond dramatically to BRAF inhibitors, others see only slight decreases in tumor size, lending credence to the idea that the tumors have an inherent resistance to the drugs rather than building up a resistance over time. More than 500 secreted factors were tested, and it was found that the factor most closely associated with resistance to BRAF inhibitor drugs was hepatocyte growth factor (HGF). The factor interacts with the MET receptor, and the abnormal activation of that receptor has been linked to tumor growth in previous studies.
Straussman says that it is unknown exactly how these healthy cells become enmeshed in the tumors.
"The cells that we used in our co-culture screen are both normal stromal cells from normal tissues (without cancer) and stromal cells that were isolated from tumors (CAFs – carcinoma associated fibroblasts)," he says. "In the melanoma example that was studied in the paper, we have clearly detected HGF-secreting stromal cells in the pre-treated tumors, but have no direct data that would indicate whether these stromal cells were recruited by the tumor or were part of the once-healthy tissue that the tumor grew in."
The researchers studied both lab-grown cells and 34 patient samples, the latter of which revealed a relationship between the amount of HGF present and how much tumors shrunk after being treated, as tumors in patients with high levels of HGF shrank less than tumors in patients with low levels.
There are currently several HGF/MET inhibitors already in clinical development or that have received U.S. Food and Drug Administration approval for other indications, and Straussman notes that "given the tolerability of those agents and the similar tolerability of BRAF inhibitors, combination clinical trials in BRAF- mutant melanoma and possibly other tumor types should be considered." He says the research team will be following up on some of the other leads that turned up in their screen, adding that "it seems that HGF is not the villain behind most of these other stroma mediate rescue phenotypes, and detailed work should be done to dissect the mechanism behind these stromal effects."
Additional contributors include senior author Todd Golub, Teppei Morikawa, Kevin Shee, Michal Barzily-Rokni, Zhi Rong Qian, Jinyan Du, Ashli Davis, Margaret M. Mongare, Joshua Gould, Dennie T. Frederick, Zachary A. Cooper, Paul B. Chapman, David B. Solit, Antoni Ribas, Roger S. Lo, Shuji Ogino and Jennifer A. Wargo.