BRAFm+ Metastatic melanoma
What makes it different, makes it vulnerable

Oncogenic addiction to BRAF mutation drives metastatic melanoma1,2

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

A closer look into the development of BRAFm+ melanoma

Watch Dr Reingard Dummer as he discusses the role of BRAF mutation in the development of melanoma

 

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 patients1,7,8

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 proliferation1,9

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

Oncogenic addiction to BRAF mutation drives metastatic melanoma

Watch Dr Reingard Dummer examine the role of the MAP kinase pathway and mutated BRAF as an oncogenic driver of disease

  1. Inamdar GS, et al. Targeting the MAPK pathway in melanoma: why some approaches succeed and other fail. Biochem Pharmacol. 2010;80(5):624-37.
  2. Pagliarini R, et al. Oncogene addiction: pathways of therapeutic response, resistance, and road maps toward a cure. EMBO Reports. 2015;16(3):280-96.
  3. Shain AH, et al. The genetic evolution of melanoma from precursor lesions. N Engl J Med. 2015;373(20):1926-36.
  4. Shain AH, et al. From melanocytes to melanomas. Nat Rev Cancer. 2016;16(6):345-58.
  5. Miller AJ, et al. Mechanisms of disease: melanoma. N Engl J Med. 2006;355(1):51-65.
  6. Jakob JA, et al. NRAS mutation status is an independent prognostic factor in metastatic melanoma. Cancer. 2012;118(16):4014-23.
  7. The Cancer Genome Atlas Network. Genomic classification of cutaneous melanoma. Cell. 2015;161(7):1681-96.
  8. Wangari-Talbot J, et al. Genetics of melanoma. Front Genet. 2013;3:330.
  9. Paluncic J, et al. Roads to melanoma: key pathways and emerging players in melanoma progression and oncogenic signaling. Biochim Biophys Acta. 2016;1863(4):770-84.