Kinase-Dead
BRAF and Oncogenic RAS
Drive Tumor Progression
through CRAF
The RAS-ERK
(extracellular
signal-regulated protein
kinase) MAPK (mitogen-activated
protein kinase)
signaling pathway
regulates cell responses
to environmental cues
that include survival,
proliferation,
senescence, and
differentiation. But, it
also plays an important
role in human cancer
when the constitutive
pathway activation
favors proliferation and
survival. In a recent
article in Cell,
Heidorn and
colleagues provide
important insight into
the genetics of human
cancer. They describe a
mechanism of
tumorigenesis mediated
by kinase-dead BRAF in
the presence of
oncogenic RAS. Using a
mouse model, the workers
showed that the
inhibition of BRAF by
chemical or genetic
means in the presence of
oncogenic or growth
factor-activated RAS
induces BRAF binding to
CRAF, leading to CRAF
hyperactivation and
consequently elevated
MEK and ERK signaling.
This does not occur when
oncogenic BRAF is
inhibited, demonstrating
that BRAF inhibition per
se does not drive
pathway activation; it
only occurs when BRAF is
inhibited in the
presence of oncogenic
RAS. Kinase-dead BRAF
mimics the effects of
the BRAF-selective drugs
and kinase-dead BRAF and
oncogenic RAS cooperate
to induce melanoma in
mice. The authors
postulate that in
RAS-mutant cells, BRAF
maintains itself in an
inactive conformation
through its own kinase
activity, either through
auto-phosphorylation or
by phosphorylating a
partner protein which
then keeps it inactive.
The results also suggest
several potential
mechanisms by which
resistance to
RAF-targeting drugs
could develop in
patients. BRAF-mutant
tumors could become
resistant to BRAF-selective
drugs if they acquire a
mutation in RAS or an
upstream component that
activates RAS, or if the
drugs select a
population of cells
harboring pre-existing
mutations in RAS.
The study
provides a molecular
basis for the design of
clinical trials using
BRAF drugs and
highlights the
importance of
understanding signaling
pathway in clinical
practice. Genetic
screening of patients
prior to administering
BRAF-selective drugs
would be required not
only to identify those
who are likely to
respond, but also to
exclude those who could
experience adverse
effects, thereby
ensuring successful
implementation of
personalized medicine.
Source:
Cell
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