2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Mechanisms of Resistance to Mitogen-
Activated Protein Kinase Pathway Inhibition
in BRAF-Mutant Melanoma
By Eva M. Goetz, PhD, and Levi A. Garraway, MD, PhD
Overview: Anticancer drug resistance remains a crucial impediment
to the care of many patients with cancer. Although
the exact mechanisms of resistance may differ for each
therapy, common mechanisms of resistance predominate,
including drug inactivation or modification, mutation of the
target protein, reduced drug accumulation, or bypass of target
inhibition. With the discovery and use of targeted therapies
(such as small-molecule kinase inhibitors), resistance has
received renewed attention—especially in light of the dramatic
responses that may emerge from such therapeutics in
particular genetic or molecular contexts. Recently, the
mitogen-activated protein kinase (MAPK) pathway has become
exemplary in this regard, since it is activated in many
different cancers. Drugs targeting RAF and MAPK kinase
(MEK) are currently in clinical trials for the treatment of
several types of cancer. Vemurafenib, a selective RAF kinase
MELANOMA IS among the most common cancers, and
with early detection and surgical resection, the 5-year
survival rate for melanoma is 98%. 1 Unfortunately, the
5-year survival rate falls to 15% for individuals with metastatic
disease. Even considering the recent spectacular therapeutic
successes, relatively few treatment options exist for
metastatic melanoma. Those in current use include chemotherapy
(dacarbazine), immunotherapy (high-dose interferon
or ipilimumab), and the newly US Food and Drug
Administration (FDA)–approved targeted therapy vemurafenib.
Therefore, new, targeted therapies are needed to
improve these dire statistics.
Approximately 40% to 60% of cutaneous melanomas contain
a V600E mutation in BRAF that results in constitutive
MAPK signaling, independent of RAS (Fig. 1). 2-4 These
melanomas are dependent on MAPK, therefore, a series of
small molecule inhibitors targeting mutant BRAF have been
developed and remain a topic of intense clinical investigation.
Vemurafenib (PLX4032) is an FDA-approved inhibitor
of BRAF(V600E), and although patients with BRAF mutation
have enjoyed a clinical benefit with vemurafenib treatment,
the fraction of patients who achieve a Response
Evaluation Criteria in Solid Tumors (RECIST) partial response
is 48%. 5 Furthermore, the average duration of response
is only 7 months. 6 Thus, the magnitude and duration
of clinical response is limited, and the development of
progressive disease after several months to approximately 1
year of treatment is nearly universal. Since mutant BRAF
melanoma is dependent on MAPK kinase/extracellular
signal-regulated kinase (MEK/ERK) signaling, MEK inhibitors
were predicted to be useful for treatment of metastatic
melanoma. Early data from phase II clinical trials of MEK
inhibitors were disappointing, however, the addition of MEK
inhibitors to RAF inhibitors provides a promising investigational
avenue, as described below. 7 Clearly, overcoming
resistance to vemurafenib may enable additional clinical
benefits to patients with BRAF(V600E) melanoma.
The development of resistance to targeted anticancer
therapy is typical in solid tumors. Several overarching
680
inhibitor recently approved for the treatment of BRAF(V600E)
melanoma, shows strong efficacy initially; however, the
development of resistance is nearly ubiquitous. In vitro testing
and analysis of patient samples have uncovered several
mechanisms of resistance to RAF inhibition. Surprisingly,
mutations in the drug-binding pocket have not thus far been
observed; however, other alterations at the level of RAF, as
well as downstream activation of MEK and bypass of MEK/
extracellular signal-regulated kinase (ERK) signaling altogether,
confer resistance to vemurafenib. Looking forward,
combined RAF and MEK inhibitor treatments may improve
efficacy—yet we must anticipate mechanisms of resistance
to this combination as well. Therefore, understanding and/or
determining the mechanism of resistance are paramount to
effective cancer treatment.
mechanisms have been described for many targeted therapies,
including erlotinib and gefitinib—epidermal growth
factor receptor (EGFR) inhibitors in non–small cell lung
cancer—and imatinib, which is used for BCR-ABL inhibition
in leukemia and KIT blockade in gastrointestinal stromal
tumors. 8-10 In studying resistance mechanisms, the overarching
goal is the development and implementation of
therapeutic combinations that can anticipate and thwart
this process at the onset of treatment, thereby increasing the
magnitude and duration of clinical benefit. Taken to its
logical conclusion, such understanding could pave the way to
durable therapeutic control of cancers driven by “druggable”
oncoprotein dysregulation.
Mechanistic Categories of Resistance to RAF Inhibition
Since resistance is so common with targeted therapies,
studies of resistance to RAF inhibitors have been at the
forefront of translational research in this area, even during
preclinical development (Table 1). Given the importance of
MAPK signaling in BRAF-mutant melanoma, it stands to
reason that any resistance mechanism leading to sustained
or reactivated MEK/ERK signaling could in principle contribute
to therapeutic resistance.
BRAF Bypass
In other genetically defined tumor subtypes, resistance
has been achieved by the acquisition of point mutations
within the oncoprotein target itself, such as the T315I
mutation in BCR-ABL resulting in resistance to imatinib,
nilotinib, and dasatinib and the T790M mutation in EGFR,
From the Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
The Broad Institute of Harvard and MIT, Cambridge, MA.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Levi A. Garraway, MD, PhD, Broad Institute of MIT
and Harvard, Dana Building, Room 1542, 44 Binney St., Boston, MA 02115; email:
levi_garraway@dfci.harvard.edu.
© 2012 by American Society of Clinical Oncology.
1092-9118/10/1-10