The
n e w e ng l a n d j o u r na l
of
m e dic i n e
edi t or i a l s
Melanoma — An Unlikely Poster Child for Personalized
Cancer Therapy
Keiran S.M. Smalley, Ph.D., and Vernon K. Sondak, M.D.
Personalized medicine has long been a mainstay
of the treatment of localized melanoma, involving surgical decisions that are individualized on
the basis of measured differences as small as
0.01 mm, as well as other biomarkers of metastatic potential, such as the presence of ulceration
or mitoses.1 Once melanoma spreads beyond the
regional nodes, however, the lack of validated
molecular targets hampers efforts to individualize therapy.
In this issue of the Journal, Flaherty and coworkers2 provide clinical proof that mutations in
the gene encoding the serine–threonine protein
kinase B-RAF (BRAF) are bona fide therapeutic
targets in melanoma. A remarkable 81% of patients whose melanomas had an activating mutation in BRAF had a response to treatment with the
new BRAF kinase inhibitor PLX4032 in a multicenter, phase 1, dose-escalation trial. Responses
to PLX4032 were dependent on mutation status,
with no complete or partial responses (according
to the Response Evaluation Criteria in Solid Tumors [RECIST]) seen in patients with melanomas
carrying wild-type BRAF. These results represent
a major breakthrough and provide proof of the
principle that the treatment of metastatic melanoma can be individualized for a substantial percentage of patients.
Over the past decade, great strides have been
made in unraveling the unique biology of melanoma, and the research investment is paying off.
The discovery in 2002 that approximately 50% of
human melanomas harbor an activating mutation
in BRAF resulting in a substitution of glutamic
acid for valine at amino acid 600 (the V600E mu-
876
tation) first raised the possibility that melanoma
may be amenable to targeted therapy.3 Since then,
extensive preclinical data have validated the V600E
mutation as an important therapeutic target in
melanoma. In parallel studies, activating mutations in the human KIT gene (encoding the v-kit
Hardy–Zuckerman 4 feline sarcoma viral oncogene
homologue) were identified in a small minority
of melanomas, and there is now evidence that
imatinib therapy leads to tumor regression in this
group of patients.4 But the very low frequency of
KIT mutations in melanoma limited the impact of
this discovery.
BRAF is an upstream component of the growthpromoting mitogen-activated protein (MAP) kinase pathway, and it is known that melanoma
cells containing mutant BRAF are dependent on
MAP kinase signaling for their growth and survival.5 Flaherty and colleagues confirmed this in
paired-biopsy studies and showed that PLX4032
effectively blocked intratumoral MAP kinase activity, leading to reduced expression of cyclin D1
and the proliferation marker Ki-67. Responses to
PLX4032 occurred in patients who had previously
received multiple chemotherapy regimens, as well
as at organ sites such as bone and liver that are
typically refractory. Overall, PLX4032 had moderate toxicity, with rash of grade 2 or 3, fatigue, and
arthralgia being the major dose-limiting toxic
effects. Somewhat unexpectedly, cutaneous squa­
mous-cell carcinomas, mostly of the keratoacanthoma type, developed in a significant percentage of patients. Even after accounting for the facts
that such tumors have been seen with the use of
other kinase inhibitors and patients with one cu-
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editorials
taneous neoplasm are at high risk of others, the
incidence of this type of squamous-cell carcinoma was quite high.
PLX4032 is not the first agent aimed at BRAF
to be evaluated for the treatment of melanoma.
The most thoroughly investigated anti-BRAF agent
to date is the multikinase inhibitor sorafenib
(Nexavar). Unlike PLX4032, sorafenib has little
single-agent activity in melanoma, and two large
trials of sorafenib and chemotherapy, as compared
with the same chemotherapy alone, showed no
significant effect of the addition of the inhibitor
(ClinicalTrials.gov numbers, NCT00111007 and
NCT00110019).6,7 This led many to question the
validity of BRAF as a target in melanoma, and
had the more specific inhibitors of mutant BRAF
been a clinical failure, the approach might well
have been abandoned.
Instead, the future holds the promise that patients with metastatic melanoma will undergo
screening, before the initiation of therapy, for the
presence of mutations in BRAF, KIT, and probably
other key genes. An important reason to confirm
the BRAF mutational status of patients comes from
the surprise finding that BRAF inhibitors paradoxically stimulate MAP kinase–mediated cell
proliferation in cell lines lacking BRAF mutations.8
Mechanistically, this seems to occur because BRAF
inhibitors have the ability to transactivate RAF1
(the v-raf-1 murine leukemia viral oncogene homologue 1, also known as CRAF),8 and this may
well underlie the frequent development of keratoacanthomas in patients receiving PLX4032. Clearly, the administration of PLX4032 or similar
BRAF inhibitors to patients whose melanomas
do not carry BRAF mutations should be avoided
for the time being.
The impressive responses seen in the study by
Flaherty and colleagues do not necessarily persist
for extended periods, although the median duration of progression-free survival was not yet
reached at the time of publication and will probably exceed 7 months. This pattern of initial response and eventual resistance is similar to that
seen with targeted therapy in other tumors. Although we currently know little about the mechanisms of resistance to PLX4032 therapy, Flaherty
and colleagues did not find that any tumors had
new or novel BRAF mutations (such as the “gatekeeper” mutations found in the epidermal growth
factor receptor after erlotinib therapy). The mech-
anisms of PLX4032 resistance may be diverse; personalized therapy may equal personalized failure.
Studies in vitro indicate that exogenous growth
factors or cytokines rescue melanoma cells from
apoptosis when BRAF is knocked down by small
interfering RNA,9 and that resistance to BRAF inhibitors can be mediated through pathway switching, wherein MAP kinase signaling is routed from
BRAF to RAF1 (Fig. 1A).10 Melanoma cells that are
resistant to BRAF inhibitors seem to remain reliant on MAP kinase signaling, and this may direct
future efforts: preclinical data already suggest that
combined inhibition of BRAF and MEK (a component of the MAP kinase pathway) abrogates the
emergence of resistance,11 and a clinical trial is
currently under way to investigate this dual approach to treating melanoma (NCT01072175).
Although much attention has focused on acquired PLX4032 resistance, in the extension cohort in the study by Flaherty and colleagues, 19%
of the patients with melanomas carrying the
V600E BRAF mutation showed evidence of intrinsic resistance (i.e., did not have an objective response on the basis of RECIST criteria). A number of mechanisms probably underlie this intrinsic
resistance; melanoma cells that either lack phosphatase and tensin homologue (PTEN) function
or possess cyclin D1 amplification may be able to
survive and proliferate when BRAF is inhibited
(Fig. 1B). These and other “escape routes” could
limit dual-inhibitor approaches as well; thus, even
more novel strategies may be needed. The recent
observation that ipilimumab, a monoclonal antibody directed against the inhibitory cytotoxic
T-lymphocyte–associated antigen 4 (CTLA4) molecule on T cells, improves survival in patients
with metastatic melanoma12 suggests the possibility of combining CTLA4 blockade with BRAF
inhibition. CTLA4 blockade also offers a viable
alternative therapy for patients who do not have a
defined mutation to target. Even for patients
whose melanomas contain mutant BRAF, decisions about therapy with an inhibitor versus ipilimumab will have to be individualized, since the
overall effect of PLX4032 therapy on survival is
still undefined.
Nonetheless, the data provided by Flaherty and
colleagues represent a major advance in the treatment of metastatic melanoma. But what’s next?
How much can we improve on these results — especially in terms of extending the duration of dis-
n engl j med 363;9 nejm.org august 26, 2010
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877
The
n e w e ng l a n d j o u r na l
A
Tumor
PI3K
PLX4032
BRAF
V600E
MEK
inhibitor
MEK
PTEN
RAF1
AKT
ERK
Apoptosis
Cyclin D1
Growth
B
PI3K
RAS
PLX4032
BRAF
V600E
MEK
inhibitor
MEK
PTEN
RAF1
AKT
ERK
Cyclin D1
Apoptosis
Amplified
Growth
COLOR FIGURE
ease control — through combination
therapy
Draft 5
8/09/10 or
even by manipulating the
dose
and schedule of
Author
Sondak
1
Fig #
single-agent therapy?13 When
should
this therapy
Inhibition of Mutated, Activated
Title
BRAF in Metastatic
be moved to the adjuvant setting?
How Melanoma
can we
ME
achieve similar success in
treating
patients
with
DE
Longo
Artist
Knoper
wild-type BRAF? The prospects
for patients with
AUTHOR PLEASE NOTE:
metastatic melanoma haveFigurenever
been
brighter,
has been redrawn
and type
has been reset
Please check carefully
but the need for further Issue
progress
through
labodate 8/26/10
ratory research and well-conducted clinical trials
is as great as — or greater than — ever.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
From the Departments of Molecular Oncology (K.S.M.S.) and
Cutaneous Oncology (K.S.M.S., V.K.S.), Moffitt Cancer Center
and Research Institute, Tampa, FL.
1. Case Records of the Massachusetts General Hospital (Case
2-2007). N Engl J Med 2007;356:285-92.
2. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated,
activated BRAF in metastatic melanoma. N Engl J Med 2010;
363:809-19.
3. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF
gene in human cancer. Nature 2002;417:949-54.
4. Hodi FS, Friedlander P, Corless CL, et al. Major response to
imatinib mesylate in KIT-mutated melanoma. J Clin Oncol 2008;
26:2046-51.
878
n engl j med 363;9
m e dic i n e
Figure 1. Intracellular Signaling Pathways in Melanoma
Known to Be Important in the Response and Resistance to Targeted Therapy.
Panel A shows two signaling pathways known to be important for the growth and progression of melanoma.
Constitutive mitogen-activated protein (MAP) kinase
signaling in the RAS–RAF–MEK–ERK pathway drives the
growth of melanoma cells through the up-regulation of
cyclin D1 expression. Treatment with PLX4032 can result
in the regression of melanomas harboring the BRAF
V600E mutation because the drug blocks the activity of
the mutant BRAF. Survival of melanoma cells and resistance to apoptosis are often mediated through the constitutive activity of phosphoinositide-3-kinase (PI3K)
and the serine–threonine protein kinase AKT, which
arises through multiple mechanisms, including loss of
expression of the tumor suppressor phosphatase and
tensin homologue (PTEN). Panel B illustrates potential
mechanisms by which BRAF V600E mutated melanomas may show intrinsic or acquired resistance to BRAF
inhibition. Increased signaling through RAF1, possibly
due to increased RAF1 expression or increased receptor
tyrosine kinase activity, restores MEK and ERK activity
and results in cyclin D1 expression. In addition, some
melanomas harboring BRAF V600E mutations may already have cyclin D1 amplification, whereas others may
have lost PTEN expression; these melanomas may be
particularly likely to manifest intrinsic resistance to
BRAF-inhibitor therapy. Since resistance to BRAF inhibitors is associated with a continued reliance on the RAS–
RAF–MEK–ERK pathway, MEK inhibitors will probably
be useful in the management of acquired resistance to
BRAF inhibitors.
Increased receptor
tyrosine kinase activity
RAS
of
5. Wellbrock C, Karasarides M, Marais R. The RAF proteins
take centre stage. Nat Rev Mol Cell Biol 2004;5:875-85.
6. Hauschild A, Agarwala SS, Trefzer U, et al. Results of a phase
III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in
patients with unresectable stage III or stage IV melanoma. J Clin
Oncol 2009;27:2823-30.
7. Flaherty KT, Lee SJ, Schuchter LM, et al. Final results of
E2603: a double-blind, randomized phase III trial comparing
carboplatin (C)/paclitaxel (P) with or without sorafenib (S) in
metastatic melanoma. J Clin Oncol 2010;28:Suppl:613s. abstract.
8. Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N. RAF
inhibitors transactivate RAF dimers and ERK signalling in cells
with wild-type BRAF. Nature 2010;464:427-30.
9. Christensen C, Guldberg P. Growth factors rescue cutaneous
melanoma cells from apoptosis induced by knockdown of mutated (V600E) B-RAF. Oncogene 2005;24:6292-302.
10. Montagut C, Sharma SV, Shioda T, et al. Elevated CRAF as a
potential mechanism of acquired resistance to BRAF inhibition
in melanoma. Cancer Res 2008;68:4853-61.
11. Paraiso KH, Fedorenko IV, Cantini LP, et al. Recovery of
phospho-ERK activity allows melanoma cells to escape from
BRAF inhibitor therapy. Br J Cancer 2010;102:1724-30.
12. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival
with ipilimumab in patients with metastatic melanoma. N Engl
J Med 2010;363:711-23.
13. Gatenby RA. A change of strategy in the war on cancer. Nature 2009;459:508-9.
Copyright © 2010 Massachusetts Medical Society.
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august 26, 2010
The New England Journal of Medicine
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