Positioning Loss of PARP1 Activity as the Central Toxic Event in BRCA-Deficient Cancer
DNA repair,
Год журнала:
2024,
Номер
144, С. 103775 - 103775
Опубликована: Окт. 19, 2024
The
mechanisms
by
which
poly(ADP-ribose)
polymerase
1
(PARP1)
inhibitors
(PARPi)s
inflict
replication
stress
and/or
DNA
damage
are
potentially
numerous.
PARPi
toxicity
could
derive
from
loss
of
its
catalytic
activity
physical
trapping
PARP1
onto
that
perturbs
not
only
function
in
repair
and
replication,
but
also
obstructs
compensating
pathways.
combined
disruption
with
either
the
hereditary
breast
ovarian
cancer
genes,
BRCA1
or
BRCA2
(BRCA),
results
synthetic
lethality.
This
has
driven
development
PARP
as
therapies
for
BRCA-mutant
cancers.
In
this
review,
we
focus
on
recent
findings
highlight
activity,
rather
than
PARPi-induced
allosteric
trapping,
central
to
efficacy
BRCA
deficient
cells.
However,
review
PARP-trapping
is
an
effective
strategy
other
genetic
deficiencies.
Together,
conclude
mechanism-of-action
unilateral;
enhanced
differentially
killing
depending
context.
Therefore,
effectively
targeting
cells
requires
intricate
understanding
their
key
underlying
vulnerabilities.
Язык: Английский
Acid-Responsive Biocompatible Hydrogel Modulating Tumor DNA Self-Repair Collaborated with Chemotherapy for Boosting STING Pathway-Associated Immunotherapy
Yan-Tong Lin,
Ran Meng,
Shi‐Man Zhang
и другие.
Nano Letters,
Год журнала:
2025,
Номер
unknown
Опубликована: Фев. 24, 2025
In
this
study,
an
acid-responsive
hydrogel
(ODCM@AZD)
encapsulating
doxorubicin
(DOX),
Mn2+,
and
AZD2281
is
rationally
engineered
for
synergistic
chemo-immunotherapy.
Notably,
ODCM@AZD
can
be
specifically
degraded
within
the
tumor
microenvironment
to
release
loaded
therapeutic
agents.
Specifically,
released
DOX
kills
cells
produce
abundant
cytoplasmic
DNA,
while
freed
inhibits
DNA
repair
pathway
of
enhance
chemotherapeutic
effect
promote
accumulation
damaged
which
further
aggravated
by
reactive
oxygen
species
(ROS)
generated
from
Mn2+-mediated
Fenton-like
reaction.
Not
only
that,
Mn2+
simultaneously
increases
sensitivity
cGAS
stimulate
cGAS-STING
synergizes
with
DOX-mediated
immunogenic
cell
death
(ICD)
initiate
powerful
antitumor
immune
responses.
More
importantly,
combination
checkpoint
blockade
(ICB)
significantly
improves
systemic
tumoricidal
immunity
potentiates
effects
on
distant
recurrent
models,
providing
a
new
idea
Язык: Английский
Role of PARP Inhibitors: A New Hope for Breast Cancer Therapy
International Journal of Molecular Sciences,
Год журнала:
2025,
Номер
26(6), С. 2773 - 2773
Опубликована: Март 19, 2025
Tumors
formed
by
the
unchecked
growth
of
breast
cells
are
known
as
cancer.
The
second
most
frequent
cancer
in
world
is
It
common
among
females.
In
2022,
2,296,840
women
were
diagnosed
with
therapy
evolving
through
development
Poly
(ADP-ribose)
polymerase
(PARP)
inhibitors,
which
offering
people
specific
genetic
profiles
new
hope
research
into
disease
continues.
focuses
on
patients
BRCA1
and
BRCA2
mutations.
This
review
summarizes
recent
mechanisms
action
PARP
inhibitors
their
implications
for
therapy.
We
how
therapeutic
applications
developing
highlight
studies
showing
effectiveness
these
medicines
whether
used
alone
or
combination.
Furthermore,
significance
customized
highlighted
enhancing
patient
outcomes
we
address
function
testing
identifying
candidates
inhibition.
Recommendations
future
areas
to
maximize
potential
also
included,
along
challenges
limits
clinical
usage.
objective
this
improve
our
comprehension
complex
interaction
between
biology
knowledge
will
help
guide
screening
approaches,
practice,
support
preventive
initiatives
at
risk.
Язык: Английский
HDAC-driven mechanisms in anticancer resistance: epigenetics and beyond
Cancer Drug Resistance,
Год журнала:
2024,
Номер
unknown
Опубликована: Ноя. 20, 2024
The
emergence
of
drug
resistance
leading
to
cancer
recurrence
is
one
the
challenges
in
treatment
patients.
Several
mechanisms
can
lead
resistance,
including
epigenetic
changes.
Histone
deacetylases
(HDACs)
play
a
key
role
chromatin
regulation
through
and
are
also
involved
resistance.
control
histone
acetylation
accessibility
regulatory
DNA
sequences
such
as
promoters,
enhancers,
super-enhancers
known
by
which
HDACs
influence
gene
expression.
Other
targets
that
not
histones
contribute
This
review
describes
contribution
that,
some
cases,
may
determine
chemotherapy
or
other
treatments.
Язык: Английский
Ginseng extract (Ginsenoside RG3) combined with STING agonist reverses TAM/M2 polarization to inhibit TNBC evolution
Industrial Crops and Products,
Год журнала:
2024,
Номер
222, С. 119589 - 119589
Опубликована: Сен. 9, 2024
Язык: Английский
Targeting DNA damage response in pancreatic ductal adenocarcinoma: A review of preclinical and clinical evidence
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer,
Год журнала:
2024,
Номер
unknown, С. 189185 - 189185
Опубликована: Сен. 1, 2024
Язык: Английский
Synergy trap for guardian angels of DNA: Unraveling the anticancer potential of phthalazinone-thiosemicarbazone hybrids through dual PARP-1 and TOPO-I inhibition
Bioorganic Chemistry,
Год журнала:
2024,
Номер
153, С. 107924 - 107924
Опубликована: Окт. 30, 2024
Язык: Английский
Advancements in Clinical Research and Emerging Therapies for Triple-Negative Breast Cancer Treatment
European Journal of Pharmacology,
Год журнала:
2024,
Номер
unknown, С. 177202 - 177202
Опубликована: Дек. 1, 2024
Язык: Английский
Application and research progress of synthetic lethality in the development of anticancer therapeutic drugs
Frontiers in Oncology,
Год журнала:
2024,
Номер
14
Опубликована: Ноя. 25, 2024
With
the
tremendous
success
of
PARP
inhibitor
olaparib
in
clinical
practice,
synthetic
lethality
has
become
an
important
field
for
discovery
and
development
anticancer
drugs.
More
more
targets
have
been
discovered
with
rapid
biotechnology
recent
years.
Currently,
many
drug
candidates
that
were
designed
developed
on
basis
concept
entered
trials.
Taking
representative
lethal
Poly
ADP-ribose
polymerase
1
(PARP1),
Werner
syndrome
helicase
(WRN)
protein
arginine
methyltransferase
5
(PRMT5)
as
examples,
this
article
briefly
discusses
application
research
progress
Язык: Английский
Replication stress marker phospho-RPA2 predicts response to platinum and PARP inhibitors in homologous recombination-proficient ovarian cancer
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Ноя. 25, 2024
ABSTRACT
Background
Ovarian
cancer
treatment
includes
cytoreductive
surgery,
platinum-based
chemotherapy,
and
often
poly
(ADP-ribose)
polymerase
(PARP)
inhibitors.
Homologous
recombination
(HR)-deficiency
is
a
well-established
predictor
of
therapy
sensitivity.
However,
over
50%
HR-proficient
tumors
also
exhibit
sensitivity
to
standard-of-care
treatments.
Currently,
there
are
no
biomarkers
identify
which
will
be
sensitive
therapy.
Replication
stress
may
serve
as
key
determinant
response.
Methods
We
evaluated
phospho-RPA2-T21
(pRPA2)
foci
via
immunofluorescence
potential
biomarker
replication
in
formalin-fixed,
paraffin-embedded
tumor
samples
collected
at
diagnosis
from
patients
treated
with
platinum
chemotherapy
(discovery
cohort:
n
=
31,
validation
244)
or
PARP
inhibitors
(n
87).
Recurrent
37)
were
analyzed.
pRPA2
scores
calculated
using
automated
imaging
analysis.
Samples
defined
pRPA2-High
if
>
16%
cells
had
≥
2
foci.
Results
In
the
discovery
cohort,
HR-proficient,
demonstrated
significantly
higher
rates
pathologic
complete
response
than
pRPA2-Low
tumors.
longer
survival
after
those
Additionally,
assay
effectively
predicted
outcomes
recurrent
samples.
Conclusion
Our
study
underscores
importance
considering
markers
alongside
HR
status
therapeutic
planning.
work
suggest
that
this
could
used
throughout
patient’s
course
expand
number
receiving
effective
while
reducing
unnecessary
toxicity.
Язык: Английский