Researchers shine light on how some melanoma tumors evade drug treatment

November 24, 2010

The past year has brought to light both the promise and the frustration of developing new drugs to treat melanoma, the most deadly form of skin cancer. Early clinical tests of a candidate drug aimed at a crucial cancer-causing gene revealed impressive results in patients whose cancers resisted all currently available treatments. Unfortunately, those effects proved short-lived, as the tumors invariably returned a few months later, able to withstand the same drug to which they first succumbed. Adding to the disappointment, the reasons behind these relapses were unclear.

Now, a research team led by scientists at the Dana-Farber Cancer Institute and the Broad Institute of Harvard and MIT has unearthed one of the key players behind such drug resistance. Published in the November 25 issue of the journal Nature, the researchers pinpoint a novel cancer gene, called COT (also known as MAP3K8), and uncover the signals it uses to drive melanoma. The research underscores the gene as a new potential drug target, and also lays the foundation for a generalized approach to identify the molecular underpinnings of drug resistance in many forms of cancer.

"In melanoma as well as several other cancers, there is a critical need to understand resistance mechanisms, which will enable us to be smarter up front in designing drugs that can yield more lasting clinical responses," said senior author Levi Garraway, a medical oncologist and assistant professor at Dana-Farber and Harvard Medical School, and a senior associate member of the Broad Institute. "Our work provides an unbiased method for approaching this problem not only for melanoma, but for any tumor type."

More than half of all melanoma tumors carry changes (called "mutations") in a critical gene called B-RAF. These changes not only alter the cells' genetic makeup, but also render them dependent on certain growth signals. Recent tests of drugs that selectively exploit this dependency, known as RAF inhibitors, revealed that tumors are indeed susceptible to these inhibitors -- at least initially. However, most tumors quickly evolve ways to resist the drug's effects.

To explore the basis of this drug resistance, Garraway and his colleagues applied a systematic approach involving hundreds of different proteins called kinases. They chose this class of proteins because of its critical roles in both normal and cancerous cell growth. Garraway's team screened most of the known kinases in humans -- roughly 600 in total -- to pinpoint ones that enable drug-sensitive cells to become drug-resistant.

The approach was made possible by a resource created by scientists at the Broad Institute and the Center for Cancer Systems Biology at Dana-Farber, including Jesse Boehm, William Hahn, David Hill and Marc Vidal. The resource enables hundreds of proteins to be individually synthesized (or "expressed") in cells and studied in parallel.

From this work, the researchers identified several intriguing proteins, but one in particular stood out: a protein called COT (also known as MAP3K8). Remarkably, the function of this protein had not been previously implicated in human cancers. Despite the novelty of the result, it was not entirely surprising, since COT is known to trigger the same types of signals within cells as B-RAF. (These signals act together in a cascade known as the MAP kinase pathway.)

While their initial findings were noteworthy, Garraway and his co-workers sought additional proof of the role of COT in melanoma drug resistance. They analyzed human cancer cells, searching for ones that exhibit B-RAF mutations as well as elevated COT levels. The scientists successfully identified such "double positive" cells and further showed that the cells are indeed resistant to the effects of the RAF inhibitor.

"These were enticing results, but the gold standard for showing that something is truly relevant is to examine samples from melanoma patients," said Garraway.

Such samples can be hard to come by. They must be collected fresh from patients both before and after drug treatment. Moreover, these pre- and post- treatment samples should be isolated not just from the same patient but also from the same tumor.

Garraway and his colleagues were fortunate to obtain three such samples for analysis, thanks to their clinical collaborators led by Keith Flaherty and Jennifer Wargo at the Massachusetts General Hospital. In two out of three cases, COT gene levels became elevated following RAF inhibitor treatment or the development of drug resistance. In other cases, high levels of COT protein were evident in tissue from patients whose tumors returned or relapsed, following drug treatment. "Although we need to extend these results to larger numbers of samples, this is tantalizing clinical evidence that COT plays a role in at least some relapsing melanomas," added Garraway.

One of the critical applications of this work is to identify drugs that can be used to overcome RAF inhibitor resistance. The findings of the Nature paper suggest that a combination of therapies directed against the MAP kinase pathway - the pathway in which both B-RAF and COT are known to act - could prove effective.

"We have no doubt that other resistance mechanisms are also going to be important in B-RAF mutant melanoma," said Garraway, "but by taking a systematic approach, we should be able to find them."
-end-
Paper cited: Johannessen CM et al., COT/MAP3K8 drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature DOI: 10.1038/nature09627

About Dana-Farber Cancer Institute

Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute. It provides adult cancer care with Brigham and Women's Hospital as Dana-Farber/Brigham and Women's Cancer Center and it provides pediatric care with Children's Hospital Boston as Dana-Farber/Children's Hospital Cancer Center. Dana-Farber is the top ranked cancer center in New England, according to U.S. News & World Report, and one of the largest recipients among independent hospitals of National Cancer Institute and National Institutes of Health grant funding.

About the Broad Institute of MIT and Harvard

The Eli and Edythe L. Broad Institute of MIT and Harvard was founded in 2003 to empower this generation of creative scientists to transform medicine with new genome-based knowledge. The Broad Institute seeks to describe all the molecular components of life and their connections; discover the molecular basis of major human diseases; develop effective new approaches to diagnostics and therapeutics; and disseminate discoveries, tools, methods and data openly to the entire scientific community.

Founded by MIT, Harvard and its affiliated hospitals, and the visionary Los Angeles philanthropists Eli and Edythe L. Broad, the Broad Institute includes faculty, professional staff and students from throughout the MIT and Harvard biomedical research communities and beyond, with collaborations spanning over a hundred private and public institutions in more than 40 countries worldwide. For further information about the Broad Institute, go to www.broadinstitute.org.

For more information, contact:

Nicole Davis, Broad Institute of MIT and Harvard
ndavis@broadinstitute.org
617-714-7152

Robbin Ray, Dana-Farber Cancer Institute
robbin_ray@dfci.harvard.edu
617-632-4090

Broad Institute of MIT and Harvard

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.