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The role of BRAF V600 mutation in melanoma
Open accessAbstract
BRAF is a serine/threonine protein kinase activating the MAP kinase/ERK-signaling pathway. About 50 % of melanomas harbors activating BRAF mutations (over 90 % V600E). BRAFV600E has been implicated in different mechanisms underlying melanomagenesis, most of which due to the deregulated activation of the downstream MEK/ERK effectors. The first selective inhibitor of mutant BRAF, vemurafenib, after highly encouraging results of the phase I and II trial, was compared to dacarbazine in a phase III trial in treatment-naïve patients (BRIM-3). The study results showed a relative reduction of 63 % in risk of death and 74 % in risk of tumor progression. Considering all trials so far completed, median overall survival reached approximately 16 months for vemurafenib compared to less than 10 months for dacarbazine treatment. Vemurafenib has been extensively tested on melanoma patients expressing the BRAFV600E mutated form; it has been demonstrated to be also effective in inhibiting melanomas carrying the V600K mutation. In 2011, both FDA and EMA therefore approved vemurafenib for metastatic melanoma carrying BRAFV600 mutations. Some findings suggest that continuation of vemurafenib treatment is potentially beneficial after local therapy in a subset of patients with disease progression (PD). Among who continued vemurafenib >30 days after local therapy of PD lesion(s), a median overall survival was not reached, with a median follow-up of 15.5 months from initiation of BRAF inhibitor therapy. For patients who did not continue treatment, median overall survival from the time of disease progression was 1.4 months. A clinical phase I/II trial is evaluating the safety, tolerability and efficacy of vemurafenib in combination with the CTLA-4 inhibitor mAb ipilimumab. In the BRIM-7 trial vemurafenib is tested in association with GDC-0973, a potent and highly selective inhibitor of MEK1/2. Preliminary data seem to indicate that an additional inhibitor of mutated BRAF, GSK2118436, might be also active on a wider range of BRAF mutations (V600E-K-D-R); actually, treatment with such a compound is under evaluation in a phase III study among stage III-IV melanoma patients positive for BRAF mutations. Overall, BRAF inhibitors were well tolerated; common adverse events are arthralgia, rash, fatigue, alopecia, keratoacanthoma or cutaneous squamous-cell carcinoma, photosensitivity, nausea, and diarrhea, with some variants between different inhibitors.
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Cites
Improved Survival with Ipilimumab in Patients with Metastatic Melanoma
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Mutations of the BRAF gene in human cancer
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Self-citationImproved survival with vemurafenib in melanoma with BRAF V600E mutation
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Distinct Sets of Genetic Alterations in Melanoma
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Connecting copper and cancer: from transition metal signalling to metalloplasia
Ge, E. J., Bush, A. I., Casini, A., Cobine, P. A., Cross, J. R., DeNicola, G. M., Dou, Q. P., Franz, K. J., Gohil, V. M., Gupta, S., et al. (2022) · Nature Reviews Cancer · doi:10.1038/s41568-021-00417-2 · Cited by 1,298
Targeting RAS–RAF–MEK–ERK signaling pathway in human cancer: Current status in clinical trials
Song, Y., Bi, Z., Liu, Y., Qin, F., Wei, Y., & Wei, X. (2023) · Genes & Diseases · doi:10.1016/j.gendis.2022.05.006 · Cited by 212
A genome-wide atlas of co-essential modules assigns function to uncharacterized genes
Wainberg, M., Kamber, R. A., Balsubramani, A., Meyers, R. M., Sinnott-Armstrong, N., Hornburg, D., Jiang, L., Chan, J., Jian, R., Gu, M., et al. (2021) · Nature Genetics · doi:10.1038/s41588-021-00840-z · Cited by 204
Adolescent and young adult patients with cancer: a milieu of unique features
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Metadata
- Authors
- Ascierto, P. A., Kirkwood, J. M., Grob, J.-J., Simeone, E., Grimaldi, A. M., Maio, M., Palmieri, G., Testori, A., Marincola, F. M., & Mozzillo, N.
- Venue
- Journal of Translational Medicine
- Published
- 2012-05-03
- Volume
- 10
- Issue
- 1
- Pages
- 85-85
- ISSN
- 1479-5876 (ISSN-L)
- OpenAlex
- W2168711434
- Cited by
- 801
- References
- 42
- FWCI
- 10.57
- Type
- journal article
- Language
- en
- Open access
- gold
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- Ascierto, P. A., Kirkwood, J. M., Grob, J.-J., Simeone, E., Grimaldi, A. M., Maio, M., Palmieri, G., Testori, A., Marincola, F. M., & Mozzillo, N. (2012). The role of BRAF V600 mutation in melanoma. Journal of Translational Medicine. https://doi.org/10.1186/1479-5876-10-85
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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