Melanoma brain metastasis: overview of current management and emerging targeted therapies

Figures & data

Figure 1. The Ras/Raf/MEK/ERK pathway is an important signaling pathway for cell growth and differentiation.

(A) Protein signaling cascade commences with the onset of Raf activation by activated growth factor receptors, leading to the induction of specific gene transcription. Homeostatic control is regulated by feedback mechanisms along each chain on the pathway. (B) Mutations in the BRAF gene results in the presence of the constitutively activated form of BRAF and the persistent activation of ERK signaling that stimulate the proliferation and survival of melanoma cells.

Figure 2. Vemurafenib.

The large molecular weight at 489.9 and the polar chlorophenyl and sulfonic acid groups may prevent this molecule from readily crossing the blood–brain barrier.

Propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2.4-difluorophenyl}-amide: C₂₃H₁₈ClF₂N₃O₃S: Mr = 489.9.

Adapted from [69].

Table 1. Known genetic mutations in melanomas.

Progression of melanoma	Gene mutation	Frequency of mutation (%)
Benign nevus	CDKN2A16/p16	21
Dysplastic nevus (superficial spreading)	APAF-1PKB/AKTMYC amplificationAPC promoter 1A hypermethylationPTEN deletion/mutation, loss of heterozygosityP53 loss/mutationN-RASGRM3CHRM3GPR98	1060–702517231030161028
Invasive melanoma	BRAF	26–70

These mutations are thought to make the oncogenesis of melanoma possible. However, the development of metastatic tumors may require additional genetic and epigenetic events.

Flaherty KT, Yasothan U, Kirkpatrick P. Vemurafenib. Nat. Rev. Drug Discov. 10(11), 811–812 (2011).

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