Uncommon BRAF mutation in melanoma sensitive to MEK inhibitor drug therapy

July 16, 2012, Vanderbilt University Medical Center

An uncommon mutation of the BRAF gene in melanoma patients has been found to respond to MEK inhibitor drugs, providing a rationale for routine screening and therapy in melanoma patients who harbor the BRAF L597 mutation.

The new study by co-first-authors Kimberly Brown Dahlman, Ph.D., Junfeng Xia, Ph.D., and Katherine Hutchinson, B.S., Vanderbilt-Ingram Cancer Center (VICC), Nashville, Tenn., was published online July 14 in Cancer Discovery. The research was led by co-senior authors William Pao, M.D., Ph.D., Jeffrey Sosman, M.D., and Zhongming Zhao, Ph.D., VICC, and Antoni Ribas, M.D., Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, Calif.

in BRAF V600E or KIT are common in about 40 percent to 50 percent of melanomas, and drugs that block or inhibit BRAF V600E were recently approved for treatment of patients with these mutations. However, there has been no effective treatment for patients with wildtype (WT) melanoma that is negative for these driver mutations.

To uncover other potentially targetable mutations, the investigators studied the tumor from a 75-year-old patient with an aggressive form of melanoma which was negative for the BRAF V600E mutation. They performed on the tumor, along with DNA from matched blood, and confirmed a mutation at BRAF L597.

To determine how many similar mutations might be overlooked by assessing only the BRAF V600 position, they analyzed the mutational status of 49 additional tumor samples negative for V600, as well as recurrent mutations in NRAS and KIT. Two of the tumors (4 percent) were found to have BRAF L597 mutations and a third tumor harbored a BRAF K601E mutation.

BRAF L597 and K601 are adjacent to V600. Since V600 are sensitive to both BRAF and MEK inhibitor drugs, the investigators tested whether the BRAF inhibitor drug vemurafenib and a MEK inhibitor drug could inhibit signals induced by these mutants in cell lines. The MEK inhibitor led to a dramatic shut down of signaling, suggesting that tumors harboring BRAF L597 and K601 mutations might benefit from treatment with MEK inhibitors.

Confirming this hypothesis, a 69-year-old patient with metastatic melanoma harboring a BRAF L597S mutation experienced significant disease shrinkage after two cycles on therapy with a MEK inhibitor drug called TAK-733, currently in Phase I clinical trials. The patient was disease progression-free after more than 24 weeks.

The authors believe these data demonstrate that BRAF L597 mutations have clinical significance in melanoma. Further study is needed to confirm these findings.

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

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 ...

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.

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 ...

BRAF addiction of thyroid cancers makes them therapeutically vulnerable

November 21, 2011
Papillary carcinoma is the most common form of thyroid cancer. Approximately one quarter of these carcinomas have mutations in the BRAF gene. The prevalence of such mutations is even greater in high-grade carcinomas, particularly ...

ASCO: Trametinib improves survival in metastatic melanoma

June 5, 2012
(HealthDay) -- For patients with metastatic melanoma with activating mutations in serine-threonine protein kinase B-RAF (BRAF), treatment with the oral selective MEK inhibitor trametinib is associated with improved progression-free ...

ASCO: Dabrafenib/Trametinib active in metastatic melanoma

May 17, 2012
(HealthDay) -- For patients with V600 BRAF-mutant solid tumors, treatment with the oral BRAF inhibitor dabrafenib and the oral MEK 1/2 inhibitor trametinib is tolerated and has clinical activity in BRAF inhibitor-naive metastatic ...

Recommended for you

Targeting the engine room of the cancer cell

June 18, 2018
Researchers at Columbia University Irving Medical Center (CUIMC) have developed a highly innovative computational framework that can support personalized cancer treatment by matching individual tumors with the drugs or drug ...

Study suggests well-known growth suppressor actually fuels lethal brain cancers

June 18, 2018
Scientists report finding a potentially promising treatment target for aggressive and deadly high-grade brain cancers like glioblastoma. But they also say the current lack of a drug that hits the molecular target keeps it ...

Researchers create novel combination as potential therapy for high-risk neuroblastoma

June 18, 2018
Researchers at VCU Massey Cancer Center in Richmond, Virginia, have identified a promising target to reverse the development of high-risk neuroblastoma and potentially inform the creation of novel combination therapies for ...

Genomics offers new treatment options for infants with range of soft tissue tumors

June 18, 2018
The genetic causes of a group of related infant cancers have been discovered by scientists at the Wellcome Sanger Institute, the University of Wuerzburg and their collaborators. Whole genome sequencing of tumours revealed ...

Standard myelofibrosis drug can awaken 'dormant' lymphoma

June 18, 2018
Most patients with myelofibrosis, a rare chronic disorder of the haematopoietic cells of the bone marrow, benefit from drugs from the JAK2 inhibitor class: symptoms are relieved, survival extended and general quality-of-life ...

Breast cancer researcher warns against online genetic tests

June 18, 2018
We have never been so fascinated by the secrets inside our cells.

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.