In Melanoma Sensitive To MEK Inhibitor Drug Therapy a Rare BRAF Mutation Detected

Rare mutation of the BRAF gene in people with melanoma has been noted to respond to MEK inhibitor drugs.

Rare mutation of the BRAF gene in people with melanoma has been noted to respond to MEK inhibitor drugs, offering a rationale for routine screening and therapy in melanoma patients who hold 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.

Improved Survival in BRAF-Mutated Melanoma With Trametinib
Trametinib, a MEK inhibitor, promotes survival in advanced melanoma patients with mutations in serine–threonine protein kinase B-RAF (BRAF).

Mutations 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 melanoma 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 whole genome sequencing 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.

Gene Mutation Adding to Melanoma Risk, Identified
Novel gene mutation possibly increasing the risk of both inherited and sporadic cases of malignant melanoma, the deadliest form of skin cancer, have been identified by a major international study.

BRAF L597 and K601 are adjacent to V600. Since V600 mutants 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 cell proliferation 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.

Research Indicates How Melanomas Respond to Immune Attacks
In a novel study, researchers at Children's Hospital Boston and Brigham and Women's Hospital (BWH) have shed light on how melanomas shield themselves from immune attack.

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

Source-Eurekalert

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