Tumour microenvironment contributes to innate RAF-inhibitor resistance
Neighbouring non-cancer cells may contribute to drug resistance in melanoma
- Date : 04 Jul 2012
- Topic : Melanoma
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 the Broad Institute, Dana-Farber Cancer 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 tumour cells, studying the interplay between cancer cells and their healthy counterparts. The research team has found that normal cells that reside within the tumour, as a part of the tumour micro-environment, may supply factors that help cancer cells grow and survive despite the presence of anti-cancer drugs. These findings appear online on 4 July 2012 in a paper published in Nature.
Non-tumour cells within the tumour micro environment may be an important source of drug resistance
To investigate how the tumour micro-environment may contribute to drug resistance, the researchers designed experiments in which cancer cells were grown in the same minuscule test tubes 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 tumours in patients show an overwhelming response to BRAF inhibitors and seem to disappear, other tumours only respond by slightly decreasing in size. The failure to shrink tumours at the outset suggests that those tumours possess some level of innate resistance – the ability to evade drugs from the beginning of 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. There are many different types of mechanisms that tumours may hijack to circumvent the effects of therapy, and no single experimental approach can capture all of these potential mechanisms. Thus, the application of complementary approaches can offer considerable synergy in terms of discovering the full spectrum of clinically relevant resistance mechanisms.
Scientists have uncovered resistance mechanisms that cancer cells develop over time – genetic changes in specific genes that may give cancer the ability to overcome the effects of a drug with time – but these acquired resistance mechanisms do not explain the innate resistance seen in many tumours.
Ravid Straussman, a post-doctoral fellow at the Broad Institute and first author of the Nature paper, explained that the team studied why only a partial response is seen in most patients. They set out to dissect this question, and the next logical step was to think beyond cancer cells. After completing systematic, high-throughput screens of more than 40 cancer cell lines, the researchers chose to focus on melanoma, looking at whether factors normal cells secrete help cancer cells resist treatment. They measured more than 500 secreted factors and found that the factor most closely linked to BRAF inhibitor drug resistance was hepatocyte growth factor (HGF). HGF interacts with the MET receptor, abnormal activation of which has been tied to tumour growth in previous studies but never to drug resistance in melanoma.
Hepatocyte growth factor most closely linked to BRAF inhibitor drug resistance
In addition to studying cells in the lab, the research team sought to replicate their findings in samples from cancer patients. Dr Keith Flaherty, director of developmental therapeutics at Massachusetts General Hospital Cancer Centre and an associate professor at Harvard Medical School, and his lab provided 34 patient samples for study. The team measured levels of HGF in these samples and saw a relationship between how much HGF was present and the amount of tumour shrinkage patients experienced. For example, tumours in patients with high levels of HGF shrank less than those in patients with low HGF levels.
Exploring in patient samples what factors in the micro-environment are not only present but functionally important in drug resistance would have been largely impossible. Coming up with candidates in the lab and then exploring relevance in humans in a targeted way is the only tractable approach.
Several HGF/MET inhibitors are in clinical development or are FDA-approved for other indications, making clinical trials combining these inhibitors with BRAF inhibitors feasible in the future. In addition, researchers could follow the same approach taken by the team to screen other drugs currently in development, identifying mechanisms of resistance and ways to counter them even before treatment begins.
According to study senior author Todd Golub, Director of the Broad's Cancer Program and Charles A. Dana Investigator in Human Cancer Genetics at the Dana-Farber Cancer Institute, and also a professor at Harvard Medical School and an investigator at Howard Hughes Medical Institute, it is crucial to systematically dissect resistance much earlier in the drug development process, so that by the time a new drug enters the clinic, oncologists have a good sense of what the likely mechanisms of resistance will be and have a strategy to combat them.
This work was supported by the Howard Hughes Medical Institute, USA NCI grants, and a Melanoma Research Alliance Team Science Award.
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