Oncogenic addiction to BRAF mutation drives melanoma^1,2

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Activating the RAF kinase

BRAF mutations occur early, and alone are sufficient to drive pre-melanoma nevi formation.³ As a key initiation event, mutated BRAF acts in concert with secondary mutations to drive progression, invasion, and metastases of melanoma.^3-5 This reliance on mutated BRAF (also called oncogene) is a process called oncogene addiction.^1,2

In melanoma, the rate of BRAF mutation varies by anatomic type (eg, cutaneous, mucosal, uveal, etc).⁶ BRAF mutations occur in approximately 50% of cutaneous melanomas, which represent the largest molecular subtype.^6,7

Genomic mutations define subtypes of cutaneous melanoma, with BRAF mutations occurring in nearly 50% of patients^1,7,8

Mutation of BRAF V600 leads to a constitutive activation of the MAPK pathway, stimulation of cellular growth, and inhibition of pro-apoptotic signals, thereby driving cellular proliferation in tumour cells.¹ One specific BRAF mutation, the T1799A transversion mutation in exon 15, results in a single amino acid substitution of a valine (V) to glutamic acid (E) at amino acid position 600 (V600E).¹ This mutation accounts for approximately 90% of all BRAF mutations in melanoma (see figure above), and enables BRAF to bypass typical regulatory mechanisms.^1,7-9 Mutations at this site make BRAF more than 10 times as active compared with wild-type BRAF.¹

Oncogenic BRAF drives uncontrolled tumour growth and proliferation^1,9

Hyperactivation of, and oncogenic addiction to, mutant BRAF makes it a key biomarker and a prime target for therapeutic intervention with targeted small molecule inhibitors.^1,9