Studies identify cell-signaling pathway alterations responsible for melanoma drug resistance

November 22, 2013, American Association for Cancer Research

Genomic profiling of treatment-resistant, BRAF-mutated melanomas revealed multiple gene alterations, mostly involving a cell-signaling pathway called the MAPK pathway, and more potent forms of existing drugs and drugs targeting the protein ERK may provide durable control of the disease, according to two studies published in Cancer Discovery, a journal of the American Association for Cancer Research.

"Currently there is not enough known about the genetic and molecular changes that may cause in melanomas harboring BRAF mutations," said Levi A. Garraway, M.D., Ph.D., associate professor in the Department of Medicine at the Dana-Farber Cancer Institute at Harvard Medical School in Boston, Mass. "We applied whole-exome and, in some cases, transcriptome sequencing to study drug-resistant melanoma samples from patients treated either with BRAF inhibitor monotherapy, or with combined BRAF and MEK inhibitors.

"Drug is solvable, but it is more complicated than we had initially assumed," added Garraway. "We are hopeful that utilizing systematic approaches in partnership with large, multi-institutional clinical collaborations, like we have done here, will help us design new therapeutic combinations. The ultimate goal is to find new and long-lasting solutions to drug-resistant melanomas and other cancers."

BRAF and MEK are proteins involved in a cell-signaling pathway called the MAPK pathway. Melanomas that harbor mutations in BRAF respond to BRAF and MEK inhibitors; however, almost all of them develop resistance to these drugs within months.

"Analyses of melanomas that were treated with monotherapy showed there are some genes that are commonly mutated, but there may be many other relevant genes that are less commonly mutated, a phenomenon we call a 'long-tail distribution,'" said Garraway. "Of the resistance genes that we could characterize, the majority seemed to affect the MAPK pathway.

"What is also intriguing is that, in a second study, we analyzed samples from melanomas that became resistant to both BRAF and MEK inhibitors, and found exactly the same kinds of alterations [in the MAPK pathway] that we saw in melanomas treated with BRAF inhibitors alone," added Garraway. "This tells us that we still may not be hitting the MAPK pathway adequately enough, possibly because of drug side effects that may occur at higher doses. It would be of great interest to test more potent BRAF and MEK inhibitors, or possibly ERK inhibitors, in future clinical trials."

In the first study, Garraway and colleagues analyzed samples of metastatic melanomas harboring the BRAF V600E mutation, collected and archived from 45 patients who received BRAF-inhibitor monotherapy, either vemurafenib or dabrafenib. In 51 percent of the samples, they detected multiple alterations in genes involved in the MAPK pathway, including the genes MEK1, MEK2, and a gene regulated by the MAPK pathway called MITF.

The researchers also found that multiple known resistance-causing mutations were sometimes observed within the same tumor, indicating BRAF-mutant melanomas may use multiple resistance mechanisms simultaneously.

In the second study, Garraway and colleagues evaluated samples from five patients whose melanomas had become resistant to combined BRAF and MEK inhibition. In three drug-resistant tumor samples, they found alterations in the MAPK pathway not seen in the pretreatment tumors, including a novel mutation in the gene MEK2. However, the alterations found in these samples were mostly similar to those found in melanomas that developed resistance to treatment with BRAF-inhibitor monotherapy.

Follow-up experimental studies using melanoma cells rendered drug-resistant in the laboratory showed that melanomas with resistance mutations in MEK1 or MEK2 were still sensitive to an inhibitor that acts on another component of the MAPK pathway, called ERK. This led the researchers to suggest that targeting ERK, in addition to BRAF and MEK, might be an effective strategy to tackle drug-resistant with BRAF mutations.

Explore further: Preclinical study indicates potential for novel inhibitor to overcome drug resistance induced by RAF, MEK inhibitors

Related Stories

Preclinical study indicates potential for novel inhibitor to overcome drug resistance induced by RAF, MEK inhibitors

April 8, 2013
A new class of investigational medicines may help to treat patients with cancers driven by mutations in genes such as BRAF or KRAS/NRAS, including those patients who have become resistant to therapies that target BRAF directly, ...

SU2C researcher identifies potential treatment option for melanoma

November 21, 2013
Stand Up To Cancer (SU2C), the charitable initiative supporting ground-breaking research aimed at getting new cancer treatments to patients in an accelerated timeframe, announces that the Allan H. (Bud) and Sue Selig Stand ...

New biomarker may help guide treatment of melanoma patients

October 22, 2013
A functional biomarker that can predict whether BRAF-mutant melanomas respond to drugs targeting BRAF could help guide the treatment of patients with these cancers, according to results presented here at the AACR-NCI-EORTC ...

New study could enhance treatments for drug-resistant melanoma

November 21, 2013
Melanoma is the deadliest form of skin cancer, killing more than 8,000 in the U.S. each year. Approximately 40 percent of advanced melanoma tumors are driven to grow by the presence of mutations in a gene known as the BRAF ...

Second mutation in BRAF-mutated melanoma doesn't contribute to resistance

April 1, 2012
A second mutation found in the tumors of patients with BRAF-mutated metastatic melanoma does not contribute to resistance to BRAF inhibitor drugs, a finding that runs counter to what scientists expected to be true.

Cutting off all points of escape for melanoma cells

September 19, 2013
Despite the success of recent approved therapeutics to treat advanced melanoma, metastatic cancer cells inevitably evolve resistance to drugs. In the journal Cell Reports, a team of researchers based at The Wistar Institute, ...

Recommended for you

Stem cell vaccine immunizes lab mice against multiple cancers

February 15, 2018
Stanford University researchers report that injecting mice with inactivated induced pluripotent stem cells (iPSCs) launched a strong immune response against breast, lung, and skin cancers. The vaccine also prevented relapses ...

Induced pluripotent stem cells could serve as cancer vaccine, researchers say

February 15, 2018
Induced pluripotent stem cells, or iPS cells, are a keystone of regenerative medicine. Outside the body, they can be coaxed to become many different types of cells and tissues that can help repair damage due to trauma or ...

Team paves the way to the use of immunotherapy to treat aggressive colon tumors

February 15, 2018
In a short space of time, immunotherapy against cancer cells has become a powerful approach to treat cancers such as melanoma and lung cancer. However, to date, most colon tumours appeared to be unresponsive to this kind ...

Can our genes help predict how women respond to ovarian cancer treatment?

February 15, 2018
Research has identified gene variants that play a significant role in how women with ovarian cancer process chemotherapy.

First comparison of common breast cancer tests finds varied accuracy of predictions

February 15, 2018
Commercially-available prognostic breast cancer tests show significant variation in their abilities to predict disease recurrence, according to a study led by Queen Mary University of London of nearly 800 postmenopausal women.

Catching up to brain cancer: Researchers develop accurate model of how aggressive cancer cells move and spread

February 15, 2018
A brief chat at a Faculty Senate meeting put two University of Delaware researchers onto an idea that could be of great value to cancer researchers.


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.