BRAF Wild-Type Melanomas with NF1 Mutations: Implications for MEK Inhibitor Therapy in Specific Molecular Subgroups
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Abstract
Cutaneous melanoma represents a highly aggressive neoplasm characterized by considerable genomic heterogeneity, with distinct molecular subsets dictating therapeutic responsiveness. While BRAF-mutant melanomas benefit from targeted BRAF/MEK inhibition, BRAF wild-type (BRAF WT) tumors lacking NRAS mutations present a therapeutic challenge, particularly those harboring neurofibromin 1 (NF1) loss-of-function alterations. This article explores the molecular landscape of NF1-mutated, BRAF WT melanomas, emphasizing the potential role of constitutive MAPK pathway activation via RAS-RAF-MEK-ERK signaling dysregulation. Emerging evidence suggests that MEK inhibitors (MEKi) may exhibit clinical efficacy in this subset, though response heterogeneity underscores the need for refined patient stratification. We discuss the mechanistic rationale for MEK inhibition in NF1-deficient melanomas, addressing predictive biomarkers, resistance mechanisms, and combinatorial strategies to optimize therapeutic outcomes in this genomically defined cohort.
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References
I. Howlader N SEER cancer statistics review, 1975–2012. Bethesda: National Cancer Institute; 2015. Available from:
http://seer.cancer.gov/csr/1975_2012/.
II. Tsao H, Atkins MB, Sober AJ. Management of cutaneous melanoma. N Engl J Med. 2004;351(10):998–1012.
III. Chapman PB et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507–16.
IV. Hauschild A et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380(9839):358–65.
V. Flaherty KT et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367(2):107–14.
VI. Exploring the pathway: the RAS/RAF/MEK/ERK pathway in cancer: combination therapies and overcoming feedback in ASCO Daily News. 2015.
VII. Platz A et al. Human cutaneous melanoma; a review of NRAS and BRAF mutation frequencies in relation to histogenetic subclass and body site. Mol Oncol. 2008;1(4):395–405.
VIII. Rosenberg SA et al. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA. 1994;271(12):907–13.
IX. Atkins MB et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999;17(7):2105–16.
X. Schwartzentruber DJ. Guidelines for the safe administration of high-dose interleukin-2. J Immunother. 2001;24(4):287–93.
XI. Hodi FS et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23.
XII. Robert C et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364(26):2517–26.
XIII. Topalian SL et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–54.
XIV. Hamid O et al. Safety and tumor responses with lambrolizumab (Anti-PD-1) in melanoma. N Engl J Med. 2013;369(2):134–44.
XV. Robert C et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014;384(9948):1109–17