Nature Communications,
Год журнала:
2023,
Номер
14(1)
Опубликована: Июнь 28, 2023
Abstract
Combination
of
anti-cancer
drugs
is
broadly
seen
as
way
to
overcome
the
often-limited
efficacy
single
agents.
The
design
and
testing
combinations
are
however
very
challenging.
Here
we
present
a
uniquely
large
dataset
screening
over
5000
targeted
agent
across
81
non-small
cell
lung
cancer
lines.
Our
analysis
reveals
profound
heterogeneity
response
tumor
models.
Notably,
rarely
result
in
strong
gain
range
observable
with
Importantly,
activity
agents
more
often
when
co-targeting
functionally
proximal
genes,
offering
strategy
for
designing
efficient
combinations.
Because
combinatorial
effect
strongly
context
specific,
specificity
should
be
achievable.
resource
provided,
together
an
additional
validation
screen
sheds
light
on
major
challenges
opportunities
building
efficacious
against
provides
opportunity
training
computational
models
synergy
prediction.
Targeting
cyclin-dependent
kinases
Cyclin-dependent
(CDKs),
in
complex
with
their
cyclin
partners,
modulate
the
transition
through
phases
of
cell
division
cycle.
Cyclin
D–CDK
complexes
are
important
cancer
progression,
especially
for
certain
types
breast
cancer.
Fassl
et
al
.
discuss
advances
understanding
biology
that
have
led
to
new
concepts
about
how
drugs
target
these
induce
cytostasis
and
suggest
possible
combinations
widen
can
be
treated.
They
also
progress
overcoming
resistance
inhibitors
application
diseases
beyond
—GKA
Nucleic Acids Research,
Год журнала:
2020,
Номер
48(22), С. 12483 - 12501
Опубликована: Окт. 14, 2020
Efficient
S
phase
entry
is
essential
for
development,
tissue
repair,
and
immune
defences.
However,
hyperactive
or
expedited
causes
replication
stress,
DNA
damage
oncogenesis,
highlighting
the
need
strict
regulation.
Recent
paradigm
shifts
conflicting
reports
demonstrate
requirement
a
discussion
of
G1/S
transition
literature.
Here,
we
review
recent
studies,
propose
unified
model
decision.
In
this
model,
competition
between
mitogen
signalling
over
course
mother
cell
cycle
constitutes
predominant
control
mechanism
daughter
cells.
Mitogens
have
distinct
sensing
periods,
giving
rise
to
three
Commitment
Points
(CP1-3).
mitogen-independent
in
G1
phase,
but
remains
sensitive
damage,
such
as
single
strand
breaks,
most
frequently-occurring
lesions
that
uniquely
threaten
replication.
To
CP1-3,
dedicated
hubs
integrate
antagonistic
mitogenic
signals,
regulating
stoichiometric
cyclin:
CDK
inhibitor
ratio
ultrasensitive
CDK4/6
CDK2.
This
combines
findings
decades
study,
provides
an
updated
foundation
research.
International Journal of Cancer,
Год журнала:
2020,
Номер
147(11), С. 2988 - 2995
Опубликована: Май 14, 2020
The
regulation
and
function
of
cyclin-dependent
kinase
6
(CDK6)-
4
(CDK4)-cyclin
complexes
are
commonly
altered
with
enhanced
activity
found
in
hematopoietic
malignancies,
breast
cancer
melanoma
making
CDK4
CDK6
attractive
targets
for
therapeutic
interference.
Although
dual
CDK4/6
inhibitors
have
revolutionized
treatment
patients
reveal
promising
results
several
solid
tumors
hematological
there
is
a
need
novel
compounds
targeting
the
versatile
kinase-independent
functions
to
improve
treatment.
following
review
summarizes
latest
findings
on
development
discusses
approaches
selectively
inhibit
CDK6s
as
transcriptional
regulator.
Journal of Hematology & Oncology,
Год журнала:
2022,
Номер
15(1)
Опубликована: Окт. 8, 2022
Abstract
The
United
States
Food
and
Drug
Administration
(US
FDA)
has
always
been
a
forerunner
in
drug
evaluation
supervision.
Over
the
past
31
years,
1050
drugs
(excluding
vaccines,
cell-based
therapies,
gene
therapy
products)
have
approved
as
new
molecular
entities
(NMEs)
or
biologics
license
applications
(BLAs).
A
total
of
228
these
were
identified
cancer
therapeutics
cancer-related
drugs,
120
them
classified
therapeutic
for
solid
tumors
according
to
their
initial
indications.
These
evolved
from
small
molecules
with
broad-spectrum
antitumor
properties
early
stage
monoclonal
antibodies
(mAbs)
antibody‒drug
conjugates
(ADCs)
more
precise
targeting
effect
during
most
recent
decade.
extended
indications
other
malignancies,
constituting
treatment
system
monotherapy
combined
therapy.
However,
available
targets
are
still
mainly
limited
receptor
tyrosine
kinases
(RTKs),
restricting
development
drugs.
In
this
review,
summarized
indications,
characteristics,
functions.
Additionally,
RTK-targeted
therapies
immune
checkpoint-based
immunotherapies
also
discussed.
Our
analysis
existing
challenges
potential
opportunities
may
advance
tumor
future.
Cancer Discovery,
Год журнала:
2021,
Номер
12(2), С. 356 - 371
Опубликована: Сен. 20, 2021
Cyclin-dependent
kinases
4
and
6
(CDK4/6)
represent
a
major
therapeutic
vulnerability
for
breast
cancer.
The
are
clinically
targeted
via
ATP
competitive
inhibitors
(CDK4/6i);
however,
drug
resistance
commonly
emerges
over
time.
To
understand
CDK4/6i
resistance,
we
surveyed
1,300
cancers
identified
several
genetic
alterations
(e.g.,
FAT1,
PTEN,
or
ARID1A
loss)
converging
on
upregulation
of
CDK6.
Mechanistically,
demonstrate
CDK6
causes
by
inducing
binding
CDK
inhibitor
INK4
proteins
p18INK4C).
In
vitro
kinase
assays
together
with
physical
modeling
reveal
that
the
p18INK4C-cyclin
D-CDK6
complex
occludes
while
only
weakly
suppressing
binding.
Suppression
expression
its
to
restores
sensitivity.
overcome
this
constraint,
developed
bifunctional
degraders
conjugating
palbociclib
E3
ligands.
Two
resulting
lead
compounds
potently
degraded
CDK4/6,
leading
substantial
antitumor
effects
in
vivo,
demonstrating
promising
potential
retargeting
CDK4/6
despite
resistance.
SIGNIFICANCE:
activation
represents
common
mechanism
which
oncogenic
signaling
induces
proliferation
is
potentially
targetable
inhibitors.
We
identify
CDK6-INK4
resilient
current-generation
develop
new
strategy
more
effective
inhibition
kinases.This
article
highlighted
This
Issue
feature,
p.
275.
