Drug-resistant melanoma tumors shrink when therapy is interrupted

January 9, 2013
This is Martin McMahon, Ph.D. Credit: Credit UCSF

Researchers in California and Switzerland have discovered that melanomas that develop resistance to the anti-cancer drug vemurafenib (marketed as Zelboraf), also develop addiction to the drug, an observation that may have important implications for the lives of patients with late-stage disease.

The team, based at the University of California, San Francisco (UCSF), the Novartis Institutes for Biomedical Research (NIBR) in Emeryville, Calif., and University Hospital Zurich, found that one mechanism by which cells become resistant to vemurafenib also renders them "addicted" to the drug. As a result, the melanoma cells nefariously use vemurafenib to spur the growth of rapidly progressing, deadly and drug-resistant tumors.

As described this week in the journal Nature, the team built upon this basic discovery and showed that adjusting the dosing of the drug and introducing an on-again, off-again treatment schedule prolonged the life of mice with melanoma.

"Remarkably, intermittent dosing with vemurafenib prolonged the lives of mice with drug-resistant melanoma tumors," said co-lead researcher Martin McMahon, PhD, the Efim Guzik Distinguished Professor of in the UCSF Helen Diller Family Comprehensive Cancer Center.

It is therefore possible that a similar approach may extend the effectiveness of the drug for people – an idea that awaits testing in clinical trials.

Investigated through a public-private partnership, the research was spearheaded by the study's first author Meghna Das Thakur, PhD, a Novartis Presidential , who was co-mentored by McMahon at UCSF and Darrin Stuart, PhD at NIBR.

McMahon is supported by the Melanoma Research Alliance, the National Cancer Institute and the UCSF Helen Diller Family Comprehensive Cancer Center, which is one of the country's leading research and clinical care centers, and is the only comprehensive cancer center in the San Francisco Bay Area.

Melanoma: A Deadly Form of Skin Cancer

Melanoma is the most aggressive type of skin cancer, and in 2012 alone, an estimated 76,250 people in the United States were newly diagnosed with it. Some 9,180 people died last year from the disease, according to the .

As with all forms of cancer, melanoma starts with normal cells in the body that accumulate mutations and undergo transformations that cause them to grow aberrantly and metastasize. One of the most common mutations in melanoma occurs in a gene called BRAF, and more than half of all people with melanoma express mutated BRAF.

In 2011, the U.S. Food and Drug Administration (FDA) approved the drug vemurafenib for patients who have late-stage melanoma with mutations in BRAF after clinical trials showed a significant increase in survival for such patients when taking the drug. The drug's benefits do not last forever, though, and while their tumors may initially shrink, most people on vemurafenib suffer cancer recurrence in the long run with a lethal, drug-resistant form of melanoma.

In the laboratory, the same phenomenon can be observed in mice. When small melanoma tumor fragments are implanted in mice, the tumors will initially shrink in response to drug, but eventually the mice will cease to respond to the drug and their tumors will re-emerge in a resistant form.

Targeting the Mechanism of Resistance

Working with such laboratory models, the UCSF and NIBR research teams were able to determine the mechanism of resistance. They discovered that when are subjected to vemurafenib, they become resistant by making more of the BRAF protein – the very target of the drug itself.

The idea for intermittent dosing came directly from this insight. If by becoming resistant to vemurafenib's anti-cancer potency, melanoma also becomes addicted to it, Das Thakur and her colleagues reasoned, then drug-resistant tumors may shrink when the vemurafenib is removed. That's exactly what they observed.

The team discovered that when they stopped administering the drug to mice with resurgent, resistant tumors, the tumors once again shrank. In addition, mice continuously treated with vemurafenib all died of drug-resistant disease within about 100 days, whereas all the mice treated with vemurafenib but with regular "drug holidays" all lived past 100 days.

"Vemurafenib has revolutionized treatment of a specific subset of melanoma expressing mutated BRAF, but its long-term effectiveness is diminished by the development of drug resistance," said McMahon, the Efim Guzik Distinguished Professor of Cancer Biology in the UCSF Helen Diller Family Comprehensive Cancer Center. "By seeking to understand the mechanisms of drug resistance, we have also found a way to enhance the durability of the response via intermittent dosing."

Explore further: New drug, Vemurafenib, doubles survival of metastatic melanoma patients

More information: The article, "Modeling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance" is authored by Meghna Das Thakur, Fernando Salangsang, Allison S. Landman, William R. Sellers, Nancy K. Pryer, Mitchell P. Levesque, Reinhard Dummer, Martin McMahon and Darrin Stuart. It appears in the Jan. 9, 2013, issue of the journal Nature. dx.doi.org/10.1038/nature11814

Related Stories

New drug, Vemurafenib, doubles survival of metastatic melanoma patients

March 1, 2012
A report published this week in the New England Journal of Medicine shows that the 50 percent of metastatic melanoma patients with a specific genetic mutation benefit from the drug Vemurafenib – increasing median survival ...

Study suggests patients should be screened before receiving vemurafenib

August 14, 2012
Different genetic mistakes driving skin cancer may affect how patients respond to the drug vemurafenib, providing grounds to screen people with melanoma skin cancer before treatment, a new study by Cancer Research UK scientists ...

Researchers discover why new melanoma drug stops working

November 24, 2011
(Medical Xpress) -- Research led by investigators at Memorial Sloan-Kettering Cancer Center has identified a previously unknown mechanism of resistance to the newly approved melanoma drug, vemurafenib, an oral targeted therapy ...

Researchers find potential solution to melanoma's resistance to vemurafenib

February 28, 2012
Researchers at Moffitt Cancer Center in Tampa, Fla., and colleagues in California have found that the XL888 inhibitor can prevent resistance to the chemotherapy drug vemurafenib, commonly used for treating patients with melanoma.

Study uncovers mechanism by which melanoma drug accelerates secondary skin cancers

January 18, 2012
Patients with metastatic melanoma taking the recently approved drug vemurafenib (Zelboraf) responded well to the twice daily pill, but some of them developed a different, secondary skin cancer. Now, researchers at UCLA's ...

P Rex-1 protein key to melanoma metastasis

November 22, 2011
Researchers from UNC Lineberger Comprehensive Cancer Center are part of a team that has identified a protein, called P-Rex1, that is key to the movement of cells called melanoblasts. When these cells experience uncontrolled ...

Recommended for you

Shooting the achilles heel of nervous system cancers

July 20, 2017
Virtually all cancer treatments used today also damage normal cells, causing the toxic side effects associated with cancer treatment. A cooperative research team led by researchers at Dartmouth's Norris Cotton Cancer Center ...

Molecular changes with age in normal breast tissue are linked to cancer-related changes

July 20, 2017
Several known factors are associated with a higher risk of breast cancer including increasing age, being overweight after menopause, alcohol intake, and family history. However, the underlying biologic mechanisms through ...

Immune-cell numbers predict response to combination immunotherapy in melanoma

July 20, 2017
Whether a melanoma patient will better respond to a single immunotherapy drug or two in combination depends on the abundance of certain white blood cells within their tumors, according to a new study conducted by UC San Francisco ...

Discovery could lead to better results for patients undergoing radiation

July 19, 2017
More than half of cancer patients undergo radiotherapy, in which high doses of radiation are aimed at diseased tissue to kill cancer cells. But due to a phenomenon known as radiation-induced bystander effect (RIBE), in which ...

Definitive genomic study reveals alterations driving most medulloblastoma brain tumors

July 19, 2017
The most comprehensive analysis yet of medulloblastoma has identified genomic changes responsible for more than 75 percent of the brain tumors, including two new suspected cancer genes that were found exclusively in the least ...

Novel CRISPR-Cas9 screening enables discovery of new targets to aid cancer immunotherapy

July 19, 2017
A novel screening method developed by a team at Dana-Farber/Boston Children's Cancer and Blood Disorders Center—using CRISPR-Cas9 genome editing technology to test the function of thousands of tumor genes in mice—has ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.