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Antiproliferative effects of CDK4/6 inhibition in CDK4-amplified human liposarcoma in vitro and in vivo.
[liposarcoma]
Well-differentiated
/
dedifferentiated
liposarcomas
(
WD
/
DDLPS
)
are
among
the
most
common
subtypes
of
soft
tissue
sarcomas
.
Conventional
systemic
chemotherapy
has
limited
efficacy
and
novel
therapeutic
strategies
are
needed
to
achieve
better
outcomes
for
patients
.
The
cyclin-dependent
kinase
4
(
CDK
4
)
gene
is
highly
amplified
in
more
than
95
%
of
WD
/
DDLPS
.
In
this
study
,
we
explored
the
role
of
CDK
4
and
the
effects
of
NVP-LEE
011
(
LEE
011
)
,
a
novel
selective
inhibitor
of
CDK
4
/
CDK
6
,
on
a
panel
of
human
liposarcoma
cell
lines
and
primary
tumor
xenografts
.
We
found
that
both
CDK
4
knockdown
by
siRNA
and
inhibition
by
LEE
011
diminished
retinoblastoma
(
RB
)
phosphorylation
and
dramatically
decreased
liposarcoma
cell
growth
.
Cell-cycle
analysis
demonstrated
arrest
at
G
0
-
G
1
.
siRNA-mediated
knockdown
of
RB
rescued
the
inhibitory
effects
of
LEE
011
,
demonstrating
that
LEE
011
decreased
proliferation
through
RB
.
Oral
administration
of
LEE
011
to
mice
bearing
human
liposarcoma
xenografts
resulted
in
approximately
50
%
reduction
in
tumor
(
18
)
F-
fluorodeoxyglucose
uptake
with
decreased
tumor
biomarkers
,
including
RB
phosphorylation
and
bromodeoxyuridine
incorporation
in
vivo
.
Continued
treatment
inhibited
tumor
growth
or
induced
regression
without
detrimental
effects
on
mouse
weight
.
After
prolonged
continuous
dosing
,
reestablishment
of
RB
phosphorylation
and
cell-cycle
progression
was
noted
.
These
findings
validate
the
critical
role
of
CDK
4
in
maintaining
liposarcoma
proliferation
through
its
ability
to
inactivate
RB
function
,
and
suggest
its
potential
function
in
the
regulation
of
survival
and
metabolism
of
liposarcoma
,
supporting
the
rationale
for
clinical
development
of
LEE
011
for
the
treatment
of
WD
/
DDLPS
.
Diseases
Validation
Diseases presenting
"primary tumor xenografts"
symptom
liposarcoma
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