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Inhibition of BRAF and MEK induces synergy in
MAPK pathway inhibition
BRAF
v600E
↑ cell proliferation
and cell survival
MEK
ERK
P
Tumoral cells
BRAF
v600
P
P
P
PP
P
P
P
RAS
RTK
P
phosphorylation
BRAFi
Vemurafenib
Dabrafenib
Encorafenib
Cobimetinib
Trametinib
Binimetinib
MEKi
à
Interest in targeting downstream effector
of MAPK pathway like MEK to reduce
resistance
Mechanisms of BRAF inhibitor
resistance
1
Major BRAF inhibitors resistance was identified
as the MAPK pathway becomes re-activated
through BRAF splice amplification, BRAF splice
variant or N-RAS mutation
Adapted from : Koeblinger et al. Future Oncology, 2017