CAMBRIDGE, Mass.—There is no shortage of concern lately forthe growing issue of drug-resistant bacteria, but there is another form ofresistance in the pharmaceutical world that's causing just as much, if notmore, of a problem: the tendency of cancer to resist and, consequently, returnafter treatment. In many forms of cancer, drug treatments and chemotherapy onlyproduce partial or temporary responses in patients, and recent research from ateam of researchers from the Broad Institute, the Dana-Farber Cancer Instituteand Massachusetts General Hospital has shed some light on the biology of drugresistance in cancer. The article, "Tumour micro-environment elicits innateresistance to RAF inhibitors through HGF secretion," was published in theonline edition of Nature July 4.
The research team has found that normal, healthy cells arepresent within tumors as part of the microenvironment, and seem to beresponsible for supplying biological factors that help cancer cells to surviveeven in the face of anti-cancer drugs. Researchers examined tumors and theirmicroenvironment by growing cancer cells in the same wells as normal cells,then exposing them to anti-cancer drugs. The cancer cells died when they weregrown alone, but when they were grown together with normal cells, the cancerouscells were shown to develop resistance to more than half of the 23 anti-cancerdrugs 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 sensitiveto the targeted agents, but that's not what we see in patients," RavidStraussman, a postdoctoral fellow at the Broad Institute and first author ofthe paper, said in a press release. "Why do we get just a partial responsein most patients? We set out to dissect this question, and the next logicalstep was to think beyond cancer cells."
The team performed systematic, high-throughput screens ofmore than 40 cancer cell lines, and chose to focus on melanoma while theyexamined the idea that biological factors secreted by normal cells might helpcancerous cells resist treatment.
"Even though recent advances in targeted therapy havecaused tremendous excitement in melanoma, the fact remains that drug resistanceeventually develops in nearly all metastatic melanomas treated with RAFinhibitors, and in some cases is present at the outset of treatment," LeviA. Garraway, a senior associate member of the Broad Institute an associateprofessor at Dana-Farber Cancer Institute and Harvard Medical School, said in apress release.
One of the common mutations in melanoma is a mutation of theBRAF gene, and while some patients respond dramatically to BRAF inhibitors,others see only slight decreases in tumor size, lending credence to the ideathat the tumors have an inherent resistance to the drugs rather than buildingup a resistance over time. More than 500 secreted factors were tested, and itwas found that the factor most closely associated with resistance to BRAFinhibitor drugs was hepatocyte growth factor (HGF). The factor interacts withthe MET receptor, and the abnormal activation of that receptor has been linkedto tumor growth in previous studies.
Straussman says that it is unknown exactly how these healthycells become enmeshed in the tumors.
"The cells that we used in our co-culture screen are bothnormal stromal cells from normal tissues (without cancer) and stromal cellsthat were isolated from tumors (CAFs – carcinoma associated fibroblasts)," hesays. "In the melanoma example that was studied in the paper, we have clearlydetected HGF-secreting stromal cells in the pre-treated tumors, but have nodirect data that would indicate whether these stromal cells were recruited bythe tumor or were part of the once-healthy tissue that the tumor grew in."
The researchers studied both lab-grown cells and 34 patientsamples, the latter of which revealed a relationship between the amount of HGFpresent and how much tumors shrunk after being treated, as tumors in patientswith high levels of HGF shrank less than tumors in patients with low levels.
There are currently several HGF/MET inhibitors already inclinical development or that have received U.S. Food and Drug Administrationapproval for other indications, and Straussman notes that "given thetolerability of those agents and the similar tolerability of BRAF inhibitors,combination clinical trials in BRAF-mutant melanoma and possibly other tumortypes should be considered." He says the research team will be following up onsome of the other leads that turned up in their screen, adding that "it seemsthat HGF is not the villain behind most of these other stroma mediate rescuephenotypes, and detailed work should be done to dissect the mechanism behindthese stromal effects."
Additional contributors include seniorauthor Todd Golub, Teppei Morikawa, Kevin Shee, Michal Barzily-Rokni, Zhi RongQian, 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.
The research was support by the Howard Hughes MedicalInstitute, grants from the National Cancer Institute and a Melanoma ResearchAlliance Team Science Award.
