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Drug synergy screen and network modeling in dedifferentiated liposarcoma identifies CDK4 and IGF1R as synergistic drug targets.
[dedifferentiated liposarcoma]
Dedifferentiated
liposarcoma
(
DDLS
)
is
a
rare
but
aggressive
cancer
with
high
recurrence
and
low
response
rates
to
targeted
therapies
.
Increasing
treatment
efficacy
may
require
combinations
of
targeted
agents
that
counteract
the
effects
of
multiple
abnormalities
.
To
identify
a
possible
multicomponent
therapy
,
we
performed
a
combinatorial
drug
screen
in
a
DDLS
-derived
cell
line
and
identified
cyclin-dependent
kinase
4
(
CDK
4
)
and
insulin-like
growth
factor
1
receptor
(
IGF
1
R
)
as
synergistic
drug
targets
.
We
measured
the
phosphorylation
of
multiple
proteins
and
cell
viability
in
response
to
systematic
drug
combinations
and
derived
computational
models
of
the
signaling
network
.
These
models
predict
that
the
observed
synergy
in
reducing
cell
viability
with
CDK
4
and
IGF
1
R
inhibitors
depends
on
the
activity
of
the
AKT
pathway
.
Experiments
confirmed
that
combined
inhibition
of
CDK
4
and
IGF
1
R
cooperatively
suppresses
the
activation
of
proteins
within
the
AKT
pathway
.
Consistent
with
these
findings
,
synergistic
reductions
in
cell
viability
were
also
found
when
combining
CDK
4
inhibition
with
inhibition
of
either
AKT
or
epidermal
growth
factor
receptor
(
EGFR
)
,
another
receptor
similar
to
IGF
1
R
that
activates
AKT
.
Thus
,
network
models
derived
from
context-
specific
proteomic
measurements
of
systematically
perturbed
cancer
cells
may
reveal
cancer
-
specific
signaling
mechanisms
and
aid
in
the
design
of
effective
combination
therapies
.
Diseases
Validation
Diseases presenting
"cooperatively suppresses"
symptom
dedifferentiated liposarcoma
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