Deleted Journal,
Год журнала:
2024,
Номер
19(2), С. 44 - 59
Опубликована: Авг. 9, 2024
The
poly
(ADP-ribose)
polymerase
(PARP)
family
of
enzymes
involves
and
regulates
various
cellular
processes
essential
functions,
such
as
apoptosis,
transcription
process,
DNA
repair.
PARPs
(PARP-1,
PARP-2,
PARP-3)
are
a
branch
familiar
proteins
that
play
crucial
role
in
repairing
damage
human
gene
involved
different
cancers
regulate
the
base
excision
repair
(BER)
pathway.
As
target-based
drug
therapy
for
cancer,
inhibition
PARP
stops
PARP-1
-2
from
damaged
mutated
cancer
cells,
eventually,
cells
die.
Considering
limited
available
therapies
treatment
advanced
recurrent
cancers,
inhibitors
(PARPi)
first
approved
drugs
particularly
target
response
to
BRCA
(BReast
CAncer
gene)-1/2
ovarian,
pancreatic,
prostate,
breast
cancers.
Recently,
six
PARPi
viz.,
olaparib,
rucaparib,
niraparib,
talazoparib,
fuzuloparib,
pamiparib
were
monotherapy
or
combination
with
other
classes
anticancer
agents
maintenance
Moreover,
appears
improve
progression-free
survival
women
platinum-sensitive
ovarian
an
adjuvant
conventional
treatment.
Importantly,
use
management
germline
BRCA1/2-associated
is
novel
therapeutic
strategy,
representing
successful
targeted
improving
outcomes
patients
hereditary
Although
resistance
these
has
been
reported
recently,
however,
strategies
have
employed
overcome
sensitivity
breast,
gastric,
prostate
International Journal of Molecular Sciences,
Год журнала:
2024,
Номер
25(2), С. 1263 - 1263
Опубликована: Янв. 19, 2024
Replication
stress
(RS)
is
a
characteristic
state
of
cancer
cells
as
they
tend
to
exchange
precision
replication
for
fast
proliferation
and
increased
genomic
instability.
To
overcome
the
consequences
improper
control,
malignant
frequently
inactivate
parts
their
DNA
damage
response
(DDR)
pathways
(the
ATM-CHK2-p53
pathway),
while
relying
on
other
which
help
maintain
fork
stability
(ATR-CHK1).
This
creates
dependency
remaining
DDR
pathways,
vulnerability
further
destabilization
synthetic
lethality
inhibitors
with
common
oncogenic
alterations
such
mutations
TP53,
RB1,
ATM,
amplifications
MYC,
CCNE1
others.
The
RS
normally
limited
by
coordination
cell
cycle,
transcription
replication.
Inhibition
WEE1
PKMYT1
kinases,
prevent
unscheduled
mitosis
entry,
leads
fragility
under-replicated
sites.
Recent
evidence
also
shows
that
inhibition
Cyclin-dependent
kinases
(CDKs),
CDK4/6,
CDK2,
CDK8/19
CDK12/13
can
contribute
through
disruption
repair
control.
Here,
we
review
main
causes
in
cancers
well
therapeutic
targets—ATR,
CHK1,
PARP
inhibitors.
Abstract
Synthetic
lethality
(SL),
a
genetic
concept,
has
revolutionized
the
development
of
antitumor
therapies
by
providing
avenues
to
target
previously
“undruggable”
targets
with
enhanced
specificity
for
tumor
cells
over
normal
tissue.
The
principles
SL
have
expanded
beyond
definitions
encompass
biological
functions,
including
genome
stability,
cell
cycle
regulation,
death
mechanisms,
cellular
metabolism,
cell–cell
interactions,
and
microenvironment
(TME).
Tumor
inactivated
survival
pathways
are
sensitive
therapeutic
inhibition
compensatory
while
remain
unaffected.
Exploiting
based
on
functional
contexts
potential
significantly
improve
cancer
patient
reducing
resistance
targeted
enhancing
efficacy
when
combined
other
treatment
modalities.
This
review
explores
underlying
mechanisms
synthetic
interactions
(SLI)
characterized
functions
in
individual
TME.
We
also
provide
comprehensive
summary
strategies
leveraging
dynamic
nature
SLI
overcome
resistance.
Additionally,
we
discuss
various
approaches
models
screening
designing
potent
agents
tailored
specific
needs
patients,
as
well
combining
drugs
treatment.
offers
valuable
insights
into
harnessing
promising
avenue
precision
therapy.
Cell Reports,
Год журнала:
2024,
Номер
43(2), С. 113803 - 113803
Опубликована: Фев. 1, 2024
Predicting
the
risk
of
cancer
mutations
is
critical
for
early
detection
and
prevention,
but
differences
in
allelic
severity
human
carriers
confound
predictions.
Here,
we
elucidate
protein
folding
as
a
cellular
mechanism
driving
mutation
tumor
suppressor
BRCA1.
Using
high-throughput
protein-protein
interaction
assay,
show
that
protein-folding
chaperone
binding
patterns
predict
pathogenicity
variants
BRCA1
C-terminal
(BRCT)
domain.
HSP70
selectively
binds
94%
pathogenic
BRCA1-BRCT
variants,
most
which
engage
more
than
HSP90.
Remarkably,
magnitude
linearly
correlates
with
loss
function.
We
identify
prevalent
class
hypomorphic
bind
moderately
to
chaperones
retain
partial
Furthermore,
signifies
greater
penetrance
earlier
onset
clinic.
Our
findings
demonstrate
utility
quantitative
biosensors
variant
folding,
phenotypic
severity,
risk.
Biomedicines,
Год журнала:
2024,
Номер
12(3), С. 593 - 593
Опубликована: Март 6, 2024
Ten
percent
of
patients
with
breast
cancer,
and
probably
somewhat
more
in
ovarian
have
inherited
germline
DNA
mutations
the
cancer
genes
BRCA1
BRCA2.
In
remaining
cases,
disease
is
caused
by
acquired
somatic
genetic
epigenetic
alterations.
Targeted
therapeutic
agents,
such
as
poly
ADP-ribose
polymerases
(PARP)
inhibitors
(PARPi),
emerged
treating
cancers
associated
BRCA
since
2014.
The
first
PARPi
was
FDA-approved
initially
for
mutations.
Deleterious
variants
BRCA1/BRCA2
homologous
recombination
deficiency
status
been
strong
predictors
response
to
a
few
solid
tumors
then.
However,
relevance
less
clear.
Somatic
BRCA-mutated
might
also
respond
this
new
class
therapeutics.
Although
related
literature
often
controversial,
recently
published
case
reports
and/or
randomized
studies
demonstrated
effectiveness
aim
review
summarize
predictive
role
provide
further
assistance
clinicians
identification
who
could
potentially
benefit
from
PARPi.
European Journal of Nuclear Medicine and Molecular Imaging,
Год журнала:
2024,
Номер
51(13), С. 4099 - 4110
Опубликована: Июль 18, 2024
Small
cell
lung
cancer
(SCLC)
is
a
highly
aggressive
tumor
with
neuroendocrine
origin.
Although
SCLC
frequently
express
somatostatin
receptor
type
2
(SSTR2),
significant
clinical
benefit
of
SSTR2-targeted
radionuclide
therapies
was
not
observed
so
far.
We
hypothesize
that
combination
treatment
PARP
inhibitor
(PARPi)
could
lead
to
radiosensitization
and
increase
the
effectiveness
therapy
in
SCLC.
Frontiers in Oncology,
Год журнала:
2025,
Номер
14
Опубликована: Янв. 6, 2025
Programmed
cell
death
(PCD)
is
closely
related
to
the
occurrence,
development,
and
treatment
of
breast
cancer.
The
aim
this
study
was
investigate
association
between
various
programmed
patterns
prognosis
cancer
(BRCA)
patients.
levels
19
different
deaths
in
were
assessed
by
ssGSEA
analysis,
these
PCD
scores
summed
obtain
PCDS
for
each
sample.
relationship
with
immune
as
well
metabolism-related
pathways
explored.
PCD-associated
subtypes
obtained
unsupervised
consensus
clustering
differentially
expressed
genes
analyzed.
prognostic
signature
(PCDRS)
constructed
best
combination
101
machine
learning
algorithm
combinations,
C-index
PCDRS
compared
30
published
signatures.
In
addition,
we
analyzed
relation
therapeutic
responses.
distribution
cells
explored
single-cell
analysis
spatial
transcriptome
analysis.
Potential
drugs
targeting
key
Cmap.
Finally,
expression
clinical
tissues
verified
RT-PCR.
showed
higher
normal.
Different
groups
significant
differences
pathways.
PCDRS,
consisting
seven
genes,
robust
predictive
ability
over
other
signatures
datasets.
high
group
had
a
poorer
strongly
associated
cancer-promoting
tumor
microenvironment.
low
exhibited
anti-cancer
immunity
responded
better
checkpoint
inhibitors
chemotherapy-related
drugs.
Clofibrate
imatinib
could
serve
potential
small-molecule
complexes
SLC7A5
BCL2A1,
respectively.
mRNA
upregulated
tissues.
can
be
used
biomarker
assess
response
BRCA
patients,
which
offers
novel
insights
monitoring
personalization
