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Aberrant AKT activation drives well-differentiated liposarcoma.
[dedifferentiated liposarcoma]
Well-differentiated
liposarcoma
(
WDLPS
)
,
one
of
the
most
common
human
sarcomas
,
is
poorly
responsive
to
radiation
and
chemotherapy
,
and
the
lack
of
animal
models
suitable
for
experimental
analysis
has
seriously
impeded
functional
investigation
of
its
pathobiology
and
development
of
effective
targeted
therapies
.
Here
,
we
show
that
zebrafish
expressing
constitutively
active
Akt
2
in
mesenchymal
progenitors
develop
WDLPS
that
closely
resembles
the
human
disease
.
Tumor
incidence
rates
were
8
%
in
p
53
wild-
type
zebrafish
,
6
%
in
p
53
heterozygotes
,
and
29
%
in
p
53
-
homozygous
mutant
zebrafish
(
P
=
0
.
013
)
,
indicating
that
aberrant
Akt
activation
collaborates
with
p
53
mutation
in
WDLPS
pathogenesis
.
Analysis
of
primary
clinical
specimens
of
WDLPS
,
and
of
the
closely
related
dedifferentiated
liposarcoma
(
DDLPS
)
subtype
,
revealed
immunohistochemical
evidence
of
AKT
activation
in
27
%
of
cases
.
Western
blot
analysis
of
a
panel
of
cell
lines
derived
from
patients
with
WDLPS
or
DDLPS
revealed
robust
AKT
phosphorylation
in
all
cell
lines
examined
,
even
when
these
cells
were
cultured
in
serum-free
media
.
Moreover
,
BEZ
235
,
a
small
molecule
inhibitor
of
PI
3
K
and
mammalian
target
of
rapamycin
that
effectively
inhibits
AKT
activation
in
these
cells
,
impaired
viability
at
nanomolar
concentrations
.
Our
findings
are
unique
in
providing
an
animal
model
to
decipher
the
molecular
pathogenesis
of
WDLPS
,
and
implicate
AKT
as
a
previously
unexplored
therapeutic
target
in
this
chemoresistant
sarcoma
.
Diseases
Validation
Diseases presenting
"small molecule inhibitor"
symptom
dedifferentiated liposarcoma
systemic capillary leak syndrome
waldenström macroglobulinemia
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