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.
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.
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
|Contact: Dagny Stuart|
Vanderbilt University Medical Center