BRAF gene mutations can be found in approximately 50% of melanomas, but the most common BRAF mutation leads to substitution at residue 600 of the protein, from valine to glutamic acid. BRAF occurs in up to 95% of all melanoma cases and can be successfully blocked by using a combination of BRAF- and MEK inhibitors. The wider availability of next-generation sequencing is revealing more non-V600 BRAF mutations, and the clinical implications of these mutations are widely unknown. In this review, we will discuss the biology of the MAPK pathway and the different types of BRAF mutations as well as their effect on MEK activation. Current literature will be reviewed including in vitro data, case reports and case series.

AimsBecause the hedgehog signalling pathway plays a major role in many types of cancer and can nowadays be targeted by specific compounds, we aimed to investigate the role of this pathway in squamous cell carcinoma of the head and neck.Methods and resultsNinety‐eight treatment‐naive head and neck cancer specimens were immunohistologically stained for SMO, GLI‐1, p53 and p16 expression and correlated with clinicopathological factors. Immunoreactivity for SMO and GLI‐1 was found in 20 (20.4%) and 52 (53.1%) cases of tumours, respectively. SMO expression correlated with GLI‐1 expression (ρ = 0.258, P = 0.010) in univariate and multivariate analysis (P = 0.007, t = 2.81). In univariate analysis, high SMO expression was associated with shorter overall survival (HR = 0.56; 95% CI = 0.32–0.98; P = 0.044) and disease‐free survival (HR = 0.53; 95% CI = 0.30–0.95; P = 0.034). In multivariate cox regression analysis SMO expression showed a trend towards an independent predictor for shorter overall survival (HR = 0.57; 95% CI = 0.30–1.05; P = 0.072) and disease‐free survival (HR = 0.53; 95% CI = 0.28–1.02; P = 0.056). In head and neck cancer patients with low tumour p16 expression, SMO expression was an independent factor for overall survival (HR = 0.49; 95% CI = 0.24–0.98; P = 0.043) and disease‐free survival (HR = 0.45; 95% CI = 0.22‐0.96; P = 0.037).ConclusionAlthough it needs to be confirmed in larger cohorts, our results suggest that targeting SMO might be a potentially therapeutic option in patients with head and neck cancer. In line, molecular pathological analyses including mutation analysis in the hedgehog pathway might point to additional therapeutic leads.

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