Inhibitors
of
cyclin-dependent
kinases
4
and
6
(CDK4/6i)
are
standard
first-line
treatments
for
metastatic
ER
+
breast
cancer.
However,
acquired
resistance
to
CDK4/6i
invariably
develops,
the
molecular
phenotypes
exploitable
vulnerabilities
associated
with
not
yet
fully
characterized.
We
developed
a
panel
CDK4/6i-resistant
cancer
cell
lines
patient-derived
organoids
demonstrate
that
subset
resistant
models
accumulates
mitotic
segregation
errors
micronuclei,
displaying
increased
sensitivity
inhibitors
checkpoint
regulators
TTK
Aurora
kinase
A/B.
RB1
loss,
well-recognized
mechanism
resistance,
causes
such
defects
confers
enhanced
inhibition.
In
these
models,
inhibition
CFI-402257
induces
premature
chromosome
segregation,
leading
excessive
errors,
DNA
damage,
death.
These
findings
nominate
inhibitor
as
therapeutic
strategy
defined
patients
who
develop
CDK4/6i.
Signal Transduction and Targeted Therapy,
Год журнала:
2023,
Номер
8(1)
Опубликована: Март 1, 2023
The
TP53
tumor
suppressor
is
the
most
frequently
altered
gene
in
human
cancers,
and
has
been
a
major
focus
of
oncology
research.
p53
protein
transcription
factor
that
can
activate
expression
multiple
target
genes
plays
critical
roles
regulating
cell
cycle,
apoptosis,
genomic
stability,
widely
regarded
as
"guardian
genome".
Accumulating
evidence
shown
also
regulates
metabolism,
ferroptosis,
microenvironment,
autophagy
so
on,
all
which
contribute
to
suppression.
Mutations
not
only
impair
its
function,
but
confer
oncogenic
properties
mutants.
Since
mutated
inactivated
malignant
tumors,
it
very
attractive
for
developing
new
anti-cancer
drugs.
However,
until
recently,
was
considered
an
"undruggable"
little
progress
made
with
p53-targeted
therapies.
Here,
we
provide
systematic
review
diverse
molecular
mechanisms
signaling
pathway
how
mutations
impact
progression.
We
discuss
key
structural
features
inactivation
by
mutations.
In
addition,
efforts
have
therapies,
challenges
encountered
clinical
development.
Frontiers in Cell and Developmental Biology,
Год журнала:
2021,
Номер
9
Опубликована: Ноя. 24, 2021
DNA
replication
must
be
precisely
controlled
in
order
to
maintain
genome
stability.
Transition
through
cell
cycle
phases
is
regulated
by
a
family
of
Cyclin-Dependent
Kinases
(CDKs)
association
with
respective
cyclin
regulatory
subunits.
In
normal
cycles,
E-type
cyclins
(Cyclin
E1
and
Cyclin
E2,
CCNE1
CCNE2
genes)
associate
CDK2
promote
G1/S
transition.
E/CDK2
complex
mostly
controls
progression
phosphorylation
specific
substrates.
Oncogenic
activation
impairs
replication,
causing
stress
damage.
As
consequence,
E/CDK2-induced
leads
genomic
instability
contributes
human
carcinogenesis.
this
review,
we
focus
on
the
main
functions
molecular
mechanisms
which
oncogenic
causes
cancer.
Trends in Biochemical Sciences,
Год журнала:
2022,
Номер
47(12), С. 1009 - 1022
Опубликована: Июль 11, 2022
Cell
cycle-dependent
gene
transcription
is
tightly
controlled
by
the
retinoblastoma
(RB):E2F
and
DREAM
complexes,
which
repress
all
cell
cycle
genes
during
quiescence.
Cyclin-dependent
kinase
(CDK)
phosphorylation
of
RB
allows
for
expression
two
sets.
The
first
set
genes,
with
peak
in
G1/S,
activated
E2F
factors
(TFs)
required
DNA
synthesis.
second
set,
maximum
G2/M,
mitosis
coordinated
MuvB
complex,
together
B-MYB
Forkhead
box
M1
(FOXM1).
In
this
review,
we
summarize
key
findings
that
established
distinct
control
mechanisms
regulating
G1/S
G2/M
mammals
discuss
recent
advances
understanding
temporal
these
genes.
Genes & Development,
Год журнала:
2022,
Номер
36(5-6), С. 278 - 293
Опубликована: Март 1, 2022
DNA
repair
and
damage
signaling
pathways
are
critical
for
the
maintenance
of
genomic
stability.
Defects
contribute
to
tumorigenesis,
but
also
render
cancer
cells
vulnerable
reliant
on
remaining
activities.
Here,
we
review
major
classes
defects
in
cancer,
instability
that
they
give
rise
to,
therapeutic
strategies
exploit
resulting
vulnerabilities.
Furthermore,
discuss
impacts
both
targeted
therapy
immunotherapy,
highlight
emerging
principles
targeting
therapy.
Signal Transduction and Targeted Therapy,
Год журнала:
2023,
Номер
8(1)
Опубликована: Сен. 8, 2023
Genome
instability
has
been
identified
as
one
of
the
enabling
hallmarks
in
cancer.
DNA
damage
response
(DDR)
network
is
responsible
for
maintenance
genome
integrity
cells.
As
cancer
cells
frequently
carry
DDR
gene
deficiencies
or
suffer
from
replicative
stress,
targeting
processes
could
induce
excessive
damages
(or
unrepaired
DNA)
that
eventually
lead
to
cell
death.
Poly
(ADP-ribose)
polymerase
(PARP)
inhibitors
have
brought
impressive
benefit
patients
with
breast
(BRCA)
mutation
homologous
recombination
deficiency
(HRD),
which
proves
concept
synthetic
lethality
treatment.
Moreover,
other
two
scenarios
inhibitor
application,
replication
stress
and
combination
chemo-
radio-
therapy,
are
under
active
clinical
exploration.
In
this
review,
we
revisited
progress
therapy
beyond
launched
first-generation
PARP
inhibitors.
Next
generation
PARP1
selective
inhibitors,
maintain
efficacy
while
mitigating
side
effects,
may
diversify
application
clinic.
Albeit
unavoidable
on-mechanism
toxicities,
several
small
molecules
checkpoints
(gatekeepers)
shown
great
promise
preliminary
results,
warrant
further
evaluations.
addition,
repair
pathways
(caretakers)
also
preclinical
development.
With
these
progresses
efforts,
envision
a
new
wave
innovations
within
come
age.
