95 / 105
T
reatment
of
advanced
melanoma
– A
changing
landscape
R
ev
A
ssoc
M
ed
B
ras
2017; 63(9):814-823
815
Viral Oncogene Homolog B (BRAF) and mitogen-activat-
ed protein kinases enzyme (MEK) inhibitors (Figure 1).
8,9
In parallel, the manipulation of the immune system by
blocking ligands and receptors that act as regulators of
the T cell activation, the so-called immune checkpoints,
exemplified by the cytotoxic T lymphocyte associated
antigen 4
(CTLA-4) and programmed cell death protein
1 (PD1) and its ligand (PD-L1) have become important
strategies to control advanced tumors (Figure 2). As a
result, objective responses can be seen in more than 50%
of the cases and the 25-35% probability of a patient being
alive has transitioned from 12 months in the era of con-
ventional chemotherapy to 48-60 months.
10
While survival of patients with advanced melanoma
has been considerably improved over a relatively short
interval (Figure 3), the near future probably holds even
more consistent advances. In this article, we will review
the results of studies that led to a change in the manage-
ment of patients with advanced melanoma and discuss
how these new agents are being incorporated into treat-
ment algorithms.
M
anipulating
signaling
pathways
in
melanoma
– T
he
use
of
BRAF
and
MEK
inhibitors
Activating mutations of the BRAF gene, which is an up-
stream component of the growth-promoting MAPK path-
way (Figure 1), are found in approximately 40 to 60% of
patients with metastatic melanoma.
7,9
In about 75 to 80%
of the cases, the mutation occurs in the region that encodes
the kinase domain and consists of the substitution of glu-
tamic acid for valine at amino acid 600 (the V600E muta-
FIGURE 1
The MAPK pathway and the role of BRAF and MEK inhibitors.
RTKS: receptor tyrosine kinases; GF: growth factor; GTP: guanosine triphosphate; NRAS: neuroblastoma RAS viral oncogene homolog; BRAF: V-Raf murine sarcoma viral oncogene homolog B;
MEK: mitogen-activated protein kinases enzyme; ERK: extracellular signal-regulated kinase.
MEK
ERK
BRAF
NRAS
GTP
GF
Cell growth
and survival
Cellular membrane
Nuclear membrane
BRAF inhibitors
MEK inhibitors
RTKS
Gene transcription