Ther Adv Med Oncol
(2012) 4(2) 61 –73
© The Author(s), 2011.
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Therapeutic Advances in Medical Oncology Review
Malignant melanoma is the sixth most common
type of new cancer in the UK and the fifth most
common in the USA [National Cancer Institute,
2010]. Although it is the least common skin cancer,
cutaneous melanoma is the most life threatening
with metastases present in 10–15% of patients at
diagnosis [National Cancer Institute - Surveillance
Epidemiology and End Results, 2010]. The annual
incidence of melanoma is escalating and in the UK
the incidence rates have increased more rapidly
than any of the top 10 cancers in men and women
[Cancer Research UK, 2010]. Patients with
advanced or metastatic disease confined to the skin,
subcutis and lymph nodes have a median overall
survival (OS) of 12 months compared with only
4–6 months for patients with visceral disease [Balch
et al. 2001]. In this setting, the reported OS rates
from studies with various chemotherapeutic agents,
including dacarbazine and temozolamide, as well as
immune modulators, is between 6 and 10 months
[Chapman et al. 1999; Eigentler et al. 2003;
Middleton et al. 2000]. The cytotoxic T-lymphocyte
antigen 4 (CTLA-4) antibody, ipilimumab, was the
first agent to demonstrate a benefit in OS in previ-
ously treated metastatic melanoma [Hodi et al.
2010] and more recently in the first-line setting in
combination with dacarbazine [Robert et al. 2011].
In addition, the selective v-raf murine sarcoma viral
oncogene homolog B1 (BRAF) inhibitor, vemu-
rafenib (PLX4032), has also demonstrated an OS
benefit compared with dacarbazine in the first-line
setting [Chapman et al. 2011]. Thus, it is the advent
of immunotherapy and agents targeting specific
genetic aberrations that have significantly improved
outcomes in malignant melanoma.
Melanoma: a heterogeneous disease
Although genetic aberrations and abnormal
activity in the mitogen-activated protein kinase
(MAPK) pathway drive tumourigenesis in the
majority of cutaneous melanomas, there is an
increasing body of evidence that other pathways
and immunological mechanisms contribute to its
Aberrant activation of the MAPK pathway has
been demonstrated in over 80% of cutaneous
melanomas due to abnormalities at various levels
along the RAS-RAF-MEK-ERK pathway [Platz
et al. 2008].
The potential for BRAF V600 inhibitors in
advanced cutaneous melanoma: rationale
and latest evidence
Charlotte Lemech, Jeffrey Infante and Hendrik-Tobias Arkenau
Abstract: Historically, patients with advanced cutaneous melanoma have a poor prognosis
and limited treatment options. The discovery of selective v-raf murine sarcoma viral
oncogene homolog B1 (BRAF) V600 mutation as an oncogenic mutation in cutaneous
melanoma and the importance of the mitogen-activated protein kinase (MAPK) pathway in
its tumourigenesis have changed the treatment paradigm for melanoma. Selective BRAF
inhibitors and now MEK inhibitors have demonstrated response rates far higher than
standard chemotherapeutic options and we review the phase I–III results for these agents
in this article. The understanding of mechanisms of resistance that may occur upstream,
downstream, at the BRAF level or bypassing the MAPK pathway provides a platform for
rational drug development and combination therapies.
Keywords: BRAF inhibitor, BRAF V600E, cutaneous melanoma, ipilimumab, MEK inhibitor,
Sarah Cannon Research
UK, 93 Harley Street,
London W1G 6AD, UK; and
University College London,
Charlotte Lemech MBBS
Sarah Cannon Research
UK, London and University
College London, London,
Jeffrey Infante MD
Sarah Cannon Research
Institute, Nashville, TN,
Therapeutic Advances in Medical Oncology 4 (2)
Activation of the Rat Sarcoma (RAS) family
GTPases by growth factors or by RAS mutation is
the first step driving this pathway. Activated RAS
proteins can complex with and activate members
of the RAF kinase family (ARAF, BRAF and
CRAF), causing subsequent phosphorylation
and activation of MEK 1 and MEK2, followed by
extracellular signal-regulated kinases (ERK1 and
ERK2) [Davies et al. 2002]. In turn, this leads to
phosphorylation of the erythroblast transformation
specific (ETS) protein family, nuclear transcrip-
tion factor activation, expression of cell-cycle
regulators such as cyclin D, finally leading to
cell-cycle progression and regulation of cellular
differentiation, senescence and apoptosis/survival
[Platz et al. 2008]. Although activity along this
pathway is essential for normal cell function,
abnormal activation of the MAPK pathway due
to mutations and aberrations at various levels has
been implicated in a number of cancer types, not
only malignant melanoma but also colorectal
cancer and borderline ovarian cancer, among
others [Davies et al. 2002].
Mutations along the MAPK pathway and other
genetic alterations have been documented in
varying frequencies in primary and metastatic
melanomas based on site, previous sun exposure,
skin damage and other factors [Curtin et al. 2005,
Long et al. 2011a].
The BRAF mutation is among the most studied,
occurring in 36–59% of primary melanomas
and 42–66% of metastatic melanomas [Houben
et al. 2004; Jakob et al. 2011; Long et al. 2011a]
and has been characterized as an oncogenic
mutation [Davies et al, 2002.; Karasarides et al.
2004]. The BRAF mutation has been demon-
strated to occur more frequently in intermit-
tently sun-exposed sites (i.e. trunk) and sites
without chronic sun-induced damage and are
also present in 10–15% of primary cases of
mucosal and acral melanomas [Curtin et al.
2005; Long et al. 2011a].
In contrast, mutational analyses of melanoma in
patients with high sun exposure and chronic sun-
induced skin damage more often have high cyclin
D1 (CCND1) and cyclin-dependent kinase 4
(CDK4) gene copy numbers. Increased CCND1
copy number has also been demonstrated in
acral melanoma (44%), lentigo maligna melanoma
(10%) and superficial spreading melanoma (6%)
[Sauter et al. 2002].
Another frequently occurring mutation is the
CKIT mutation, specifically in melanomas of both
ultraviolet (UV)-protected sites, acral and mucosal
melanomas (in 36% and 39%, respectively), as well
as melanoma on chronically sun-damaged skin
(28%) [Curtin et al. 2006].
Increased copy number of GAB2, a scaffolding
protein that mediates interactions with various
signalling pathways, including RAS-RAF-MEK-
ERK and phosphoinositide 3-kinase (PI3K)-
AKT signalling, has also been demonstrated in up
to 26% of acral and mucosal melanomas and is
mutually exclusive of BRAF, NRAS and KIT
mutations [Chernoff et al. 2009]. NRAS muta-
tions have been demonstrated in 20–29% of
melanomas of all subtypes and are associated
with a higher Clark level of invasion and older age
compared with BRAF mutation tumours [Curtin
et al. 2006; Edlundh-Rose et al. 2006].
Improved understanding of the genetic heteroge-
neity in melanoma, the detection of oncogenic
mutations and the ability to target these mutations
has dramatically expanded the treatment options
available for this disease.
Types of BRAF mutations
BRAF is a serine/threonine protein kinase, encoded
on chromosome 7q34, that activates the MAPK/
ERK signalling pathway. There are now over 100
somatic mutations identified in BRAF [Wellcome
Trust Sanger Institute, 2011].
The most common somatic mutation, found in
66–90% of BRAF-mutant melanomas [Cheng
et al. 2011; Wellcome Trust Sanger Institute,
2011; Long et al. 2011a], occurs in the activating
segment in exon 15 and involves the substitution
of glutamic acid for valine at codon 600 (GTG
to GAG, known as V600E] [Davies et al. 2002;
Platz et al. 2008]. This leads to elevated kinase
activity compared with BRAF wild type (wt) dis-
ease, stimulated phosphorylation of downstream
endogenous ERK and subsequent cellular prolif-
eration and survival [Davies et al. 2002; Dhomen
and Marais, 2009].
A number of other clinically relevant, but less
common mutations have also been described,
including V600K and V600G/R. The V600K
mutation has been reported in 16–30% of patients
with BRAF-mutant metastatic melanoma [Cheng
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