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2015 Chabner Colloquium: Collaboration in Cancer Trials
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Emerging Therapies to Optimize MAP Kinase Blockade and Intercept
Compensatory Signaling
Keith T. Flaherty
Massachusetts General Hospital Cancer Center, Harvard Medical School
Keith T. Flaherty
Cancers that harbor BRAF mutations, and RAS
mutations to a lesser extent, are considered the
most MAP kinase-dependent of tumors. Melanoma is the tumor type that most commonly
harbors activating mutations in BRAF (50%)
and RAS (25%). Clinical evidence shows that
MEK inhibitors produce similar response rates
in either subpopulation (∼20%) of patients with
BRAF-mutant or RAS-mutant melanoma. BRAF
inhibitors, such as vemurafenib and dabrafenib,
have a higher therapeutic index in BRAF-mutant
melanoma than MEK inhibitors. In a metaanalysis of phase II and III trials in patients with
melanoma with BRAF-activating mutations,
treatment with a BRAF inhibitor substantially
improved overall survival (OS) compared with
standard chemotherapy.8 Furthermore, combination therapy with a BRAF inhibitor and a MEK
inhibitor resulted in improved OS compared
with BRAF inhibition alone.1
In the era of potent immunotherapies
for melanoma, oncogene-targeted therapy
plays an important therapeutic role for select
patients. In patients with BRAF Val600mutated metastatic melanoma, combination
therapy with dabrafenib and the MEK inhibitor trametinib significantly improved median
OS (25.1 months vs 18.7 months; HR, 0.71; P =
0.0107) and progression-free survival (PFS) (11
months vs 8.8 months; HR, 0.67; P < 0.001) compared with dabrafenib alone.2
Overcoming Treatment Resistance
Many patients with BRAF-mutated metastatic melanoma who demonstrate a clinical response to BRAF inhibitor monotherapy
maintain a substantial burden of residual disease.3 One explanation for the heterogeneity
of response involves acquired resistance to
BRAF inhibition. Resistance to BRAF inhibitors
readily develops through CRAF. This creates
the opportunity to deploy MEK inhibitors with
this class of BRAF inhibitors but also highlights
the opportunity for RAF inhibitors that inhibit
both BRAF and CRAF. The potential for dual
BRAF/CRAF inhibitors to have a greater therapeutic index than MEK inhibitors rests, in part,
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on putative MEK-independent functions of
CRAF that have yet to be validated in the therapeutic resistance setting.
Additional routes of escape from BRAF,
MEK, and ERK inhibition in BRAF-mutated melanoma cells involves the activation of a cyclicAMP (cAMP)-dependent signaling network.4
Activation of transcription factors downstream from the MAPK pathway, most notably microphthalmia-associated transcription
factor (MITF), also appeared to confer resistance.4 MITF directly regulates the expression
of peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1α), the mitochondrial master regulator. Activation of the BRAF/
MAPK pathway in melanoma cells is associated
with suppression of MTIF and PGC1α, as well as
decreased oxidative metabolism. Conversely,
BRAF inhibition renders BRAF-mutated melanocytes addicted to oxidative phosphorylation. This metabolic adaptation appears to
limit the efficacy of BRAF inhibitors. Additional
mechanisms, such as increased expression of
BCL2A1, a lineage-specific antiapoptotic melanoma oncogene, may also facilitate escape
from BRAF inhibition in BRAF-mutated melanoma cells.
Emerging MAP Kinase Pathway
Targets
Reactivation of the MAP kinase pathway
remains a dominant theme in patients treated
with BRAF and MEK inhibitors, suggesting
that there is an increasing role for additional
agents targeting this pathway. These include
both monotherapies as well as oncogenetargeted doublets. Emerging options for MAP
kinase pathway antagonism are summarized
in Table 1.
ERK inhibitors are in late phase I development and appear to produce toxicities similar
to MEK inhibitors. However, these agents have
yet to be established as being uniquely capable
of controlling MAP kinase pathway output and
overcoming resistance mechanisms that pertain to MEK inhibitors. HSP90 antagonists are
receiving renewed attention as a strategy to
© Society for Translational Oncology 2016
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Emerging Therapies to Optimize MAP Kinase Blockade and Intercept Compensatory Signaling
Table 1. Future Directions for MAP Kinase Pathway Antagonism
Novel MEK or ERK inhibitors
Addition of HSP90 inhibitor
Inhibition of RAF dimerization
Disrupting scaffolding functions of MAPK components
HSP90, heat-shock protein 90; MAPK, MAP kinase.
downregulate expression of mutant BRAF and wild-type BRAF
and CRAF in combination with kinase inhibitors. Preclinical
data support the potential of this approach.
New tools are needed to monitor output of the MAP
kinase pathway to understand the state of patients’ tumors
through the course of therapy and to recognize the points at
which new agents or alterations in treatment schedules are
needed. Single-cell, bulk tumor, and noninvasive imaging
strategies are all in development and may facilitate clinical
research in this area.
Future Directions
Using BRAF-mutant melanoma as the prototype, the goal is
to extend newly tested treatment principles to patients with
other BRAF-mutant tumor types. For instance, BRAF inhibitor-based treatment regimens such as vemurafenib monotherapy and combination dabrafenib/trametinib have shown
activity in patients with BRAF-mutant colorectal cancer.5,6 In
the future, the use of biomarkers, drug-sensitivity testing (in
vivo or ex vivo), and retesting of serial biopsies after lead-in
therapy may guide the selection of immunotherapy or oncogene-targeted therapy at each stage of disease.
Financial Disclosures
Dr. Flaherty discloses the following financial relationships:
Consultant/advisory role: GSK, Novartis, Roche, Sanofi,
Merck, Momenta, and Raze. Ownership interests: Clovis and
Loxo.
References
1. Ugurel S, et al. 2016. In press.
2. Long G V, Stroyakovskiy D, Gogas H, et al.
Dabrafenib and trametinib versus dabrafenib and
placebo for Val600 BRAF-mutant melanoma: a
multicentre, double-blind, phase 3 randomised
controlled trial. Lancet (London, England).
2015;386(9992):444-451.
3. Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600-mutant advanced mela-
noma treated with vemurafenib. N Engl J Med.
2012;366(8):707-714.
BRAF-mutant metastatic colorectal cancer. J Clin
Oncol. 2015;23(Suppl 3); Abstract TPS790.
4. Johannessen CM, Johnson LA, Piccioni F, et
al. A melanocyte lineage program confers resistance to MAP kinase pathway inhibition. Nature.
2013;504(7478):138-142.
6. Corcoran RB, Falchook GS, Infante JR, et al.
BRAF V600 mutant colorectal cancer expansion
cohort from the phase I/II clinical trial of BRAF
inhibitor dabrafenib (GSK2118436) plus MEK
inhibitor trametinib (GSK1120212). J Clin Oncol.
2012;30 (Suppl): Abstract 3.
5. Kopetz S, McDonough S, Morris VK, et al.
S1406: Randomized phase II study of irinotecan
and cetuximab with or without vemurafenib in
© Society for Translational Oncology 2016
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