Discovery of uncommon BRAF mutation in melanoma sensitive to MEK inhibition
A rationale for routine screening and therapy in melanoma patients who harbour the BRAF L597 mutation should be confirmed by further testing
- Date : 26 Jul 2012
- Topic : Sarcomas
An uncommon mutation of the BRAF gene, BRAF L597, has been found to respond to MEK inhibitors, providing a rationale for routine screening and therapy in melanoma patients who harbour this mutation.
The new study by co-first-authors Kimberly Brown Dahlman, PhD, Junfeng Xia, PhD, and Katherine Hutchinson, BS of the Vanderbilt-Ingram Cancer Centre (VICC), Nashville, USA, was published online July 14 in Cancer Discovery. The research was led by co-senior authors Dr William Pao, Dr Jeffrey Sosman, and Zhongming Zhao, PhD, of the VICC, and Dr Antoni Ribas of the Jonsson Comprehensive Cancer Centre, UCLA, Los Angeles.
Uncovering potentially targetable mutations
Mutations in BRAF V600E or KIT are common in about 40% to 50% of melanomas, and drugs that block or inhibit BRAF V600E were recently approved for treatment in melanoma patients with these mutations. However, there has been no effective treatment for patients with wild-type (wt) melanoma that is negative for these driver mutations.
To uncover other potentially targetable mutations, the investigators studied the tumour 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 tumour, 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 analysed the mutational status of 49 additional tumour samples negative for V600, as well as recurrent mutations in NRAS and KIT. Two of the tumours (4%) were found to have BRAF L597 mutations and a third tumour harboured 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 vemurafenib and a MEK inhibitor could inhibit cell proliferation signals induced by these mutants in cell lines. The MEK inhibitor led to a dramatic shut down of signalling, suggesting that tumours harbouring BRAF L597 and K601 mutations might benefit from treatment with MEK inhibitors.
Confirming this hypothesis, a 69 year old patient with metastatic melanoma harbouring a BRAF L597S mutation experienced significant disease shrinkage after two cycles on therapy with a MEK inhibitor 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. Funding for this research was provided by the USA National Cancer Institute (NCI), a division of the National Institutes of Health (NIH) - VICC Cancer Centre Core Grant (CA68485), 5K24 CA97588‐06 and P01CA129243, the T.J. Martell Foundation, the Kleberg Foundation, the Seaver Institute, the Wesley Coyle memorial fund, the Garcia‐Corsini family fund, Harry J. Lloyd Charitable Trust, the American Cancer Society, Stand Up to Cancer SU2C-AACR-IRG0109, The James C. Bradford Family Foundation, and an anonymous donor.
Treatment with TAK‐733 was supported through a clinical trial from Millennium Pharmaceuticals.
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