Background:
Pancreatic
ductal
adenocarcinoma
(PDAC)
is
a
devastating
disease
with
limited
number
of
known
driver
mutations
but
considerable
cancer
cell
heterogeneity.
Phosphoproteomics
provides
direct
read-out
aberrant
signalling
and
the
resultant
clinically
relevant
phenotype.
Methods:
Mass
spectrometry
(MS)-based
proteomics
phosphoproteomics
were
applied
to
42
PDAC
tumors.
To
this
end,
protein
lysates
subjected
tryptic
digestion
sequential
phosphopeptide
capture
using
pY
antibodies
IMAC
beads
followed
by
nanoLC-MS/MS
database
searching.
Functional
data
mining
was
performed
Integrative
iNferred
Kinase
Activity
(INKA)
scoring,
ssGSEA
PTM-SEA.
subtypes
investigated
consensus
clustering.
The
collected
correlated
genomic
patient
survival
outcomes.
Findings:
Data
encompassed
over
19936
pS/T
(in
5412
phosphoproteins)
1208
sites
501
total
3756
proteins.
Proteome
identified
three
distinct
tumor
intrinsic
stromal
features.
Subsequently,
phospho-subtypes
apparent:
two
tumour-intrinsic
(Phos1/2)
one
(Phos3),
resembling
molecular
subtypes.
Phos
displayed
differential
phosphorylation
signals
kinase
activity,
such
as
FGR
GSK3
activation
in
Phos1,
SRC
family
EPHA2
Phos2,
EGFR,
INSR,
MET,
ABL1,
HIPK1,
JAK
PRKCD
Phos3.
activity
analysis
an
external
cohort
supported
our
findings
underscored
importance
PI3K/AKT
ERK
pathways,
among
other.
Interestingly,
unfavorable
prognosis
higher
RTK,
MAPK
CDK
high
proliferation,
whereas
long
associated
MYLK,
ILK,
PTK6
previously
unknown.
Interpretation:
Subtype-associated
profiles
can
guide
therapeutic
combination
approaches
tumour
stroma
enriched
tissues,
emphasize
critical
role
parallel
pathways.
In
addition,
profiling
identifies
potential
markers
prognostic
significance.Funding:
This
project
Dutch
Cancer
Society
(KWF
Kankerbestrijding,
grant
KWF2016-1
/
10212
C.R.J.,
M.F.B.
E.G.).
Center
Amsterdam
Netherlands
Organisation
for
Scientific
Research
(NWO-Middelgroot
91116017)
are
acknowledged
support
mass
infrastructure
Surfsara
computing
(reference
e-infra180166).Declaration
Interest:
has
received
research
funding
from
Celgene,
Frame
Therapeutics,
Lead
Pharma.
He
acted
consultant
Servier.
Ethical
Approval:
Tumor
tissue
specimens,
snap-frozen
liquid
nitrogen
stored
at
-80°C,
retrospectively
archive
Department
Pathology
(approved
Committee
Review
Biobanks,
CTB.2015-081)
purpose
phosphoproteomic
research.
Retrospective
collection
conducted
accordance
ethical
guidelines
UMC
Code,
based
on
'Code
conduct
Health
Research'
(Dutch
Regulation
Research).
Future Medicinal Chemistry,
Год журнала:
2024,
Номер
16(3), С. 271 - 289
Опубликована: Янв. 25, 2024
Pancreatic
ductal
adenocarcinoma
(PDAC)
is
among
the
leading
causes
of
cancer-related
deaths
worldwide.
Focal
adhesion
kinase
(FAK)
a
nonreceptor
tyrosine
often
overexpressed
in
PDAC.
FAK
has
been
linked
to
cell
migration,
survival,
proliferation,
angiogenesis
and
adhesion.
This
review
first
highlights
chemoresistant
nature
Second,
role
PDAC
cancer
progression
resistance
carefully
described.
Additionally,
it
discusses
recent
developments
inhibitors
as
valuable
drugs
treatment
PDAC,
with
focus
on
diamine-substituted-2,4-pyrimidine-based
compounds,
which
represent
most
potent
class
clinical
trials
for
disease.
To
conclude,
relevant
computational
studies
performed
are
reported
highlight
key
structural
features
required
interaction
protein,
aim
optimizing
this
novel
targeted
therapy.
Cancer Letters,
Год журнала:
2024,
Номер
588, С. 216800 - 216800
Опубликована: Март 14, 2024
Drug
development
in
oncology
is
highly
challenging,
with
less
than
5%
success
rate
clinical
trials.
This
alarming
figure
points
out
the
need
to
study
more
details
multiple
biological
effects
of
drugs
specific
contexts.
Indeed,
comprehensive
assessment
drug
poly-pharmacology
can
provide
insights
into
their
therapeutic
and
adverse
effects,
optimize
utilization
maximize
Recent
technological
advances
have
made
possible
in-depth
investigation
poly-pharmacology.
review
first
highlights
high-throughput
methodologies
that
been
used
unveil
new
mechanisms
action
existing
drugs.
Then,
we
discuss
how
emerging
chemo-proteomics
strategies
allow
effectively
dissecting
an
unsupervised
manner.
Expert Review of Anticancer Therapy,
Год журнала:
2024,
Номер
24(7), С. 525 - 565
Опубликована: Май 20, 2024
Introduction
Despite
the
considerable
progress
made
in
cancer
treatment
through
development
of
target
therapies,
pancreatic
ductal
adenocarcinoma
(PDAC)
continues
to
exhibit
resistance
this
category
drugs.
As
a
result,
chemotherapy
combination
regimens
remain
primary
approach
for
aggressive
cancer.
Scientific Reports,
Год журнала:
2025,
Номер
15(1)
Опубликована: Янв. 17, 2025
Bladder
cancer
often
recurs,
necessitating
innovative
treatments
to
reduce
recurrence.
We
investigated
non-thermal
plasma's
potential
as
a
novel
anti-cancer
therapy,
focusing
on
plasma-activated
solution
(PAS),
created
by
exposing
saline
plasma.
Our
study
aims
elucidate
the
biological
effects
of
PAS
bladder
cell
lines
in
vitro,
well
combination
with
mitomycin
C
(MMC),
using
clinically
relevant
settings.
treatment
exerts
potent
cytotoxic
effect
through
production
intracellular
reactive
oxygen
species,
resulting
DNA
damage
and
subsequent
induction
G1
cycle
arrest/senescence.
This
is
induced
via
upregulation
checkpoint
signalling
repair
pathways
LC-M/MS-based
phospho-proteomics.
Importantly,
combining
MMC
reveals
synergistic
(Combination
Index
0.59-0.67),
suggesting
utilizing
therapies.
findings
demonstrate
PAS's
mode
action
suggest
its
promising
for
cancer,
warranting
further
clinical
studies.
Biomolecules,
Год журнала:
2025,
Номер
15(5), С. 693 - 693
Опубликована: Май 10, 2025
Precision
oncology
is
becoming
a
mainstay
in
the
standard
of
care
for
cancer
patients.
Recent
technological
advancements
have
significantly
lowered
cost
various
tumor
profiling
approaches,
broadening
reach
molecular
diagnostics
and
improving
patient
access
to
precision
oncology.
In
parallel,
drug
development
discovery
pipelines
continue
evolve,
driving
targeted
therapeutic
options
forward.
Yet,
not
all
patients
harboring
actionable
alterations
respond
these
interventions,
existing
therapies
do
cover
entire
spectrum
potential
targets.
this
review,
we
examine
current
suite
omics
technologies
employed
clinical
settings
underscore
their
roles
deepening
our
understanding
biology
optimizing
stratification
treatments.
We
also
highlight
relevant
trials
share
own
experiences
using
multi-omics
data
within
board
framework.
Finally,
discuss
areas
future
exploration
aimed
at
propelling
new
heights.
Metabolites,
Год журнала:
2023,
Номер
13(10), С. 1064 - 1064
Опубликована: Окт. 9, 2023
The
integrated
stress
response
is
a
signaling
network
comprising
four
branches,
each
sensing
different
cellular
stressors,
converging
on
the
phosphorylation
of
eIF2α
to
downregulate
global
translation
and
initiate
recovery.
One
these
branches
includes
GCN2,
which
senses
amino
acid
insufficiency
participates
in
maintaining
homeostasis.
Previous
studies
have
shown
that
GCN2
viable
cancer
target
when
induced
by
inhibiting
an
additional
target.
In
this
light,
we
screened
numerous
drugs
for
their
potential
synergize
with
inhibitor
TAP20.
drug
sensitivity
six
cell
lines
panel
25
compounds
was
assessed.
Each
compound
then
combined
TAP20
at
concentrations
below
IC50,
impact
growth
evaluated.
strongly
synergistic
combinations
were
further
characterized
using
synergy
analyses
matrix-dependent
invasion
assays.
Inhibitors
proteostasis
MEK-ERK
pathway,
as
well
pan-CDK
inhibitors,
flavopiridol,
seliciclib,
potently
two
lines.
Among
common
CDK
targets
CDK7,
more
selectively
targeted
THZ-1
synergized
Moreover,
partially
assessed
However,
alone
sufficient
restrict
its
growth-inhibitory
IC50.
We
conclude
inhibition
can
be
explored
vivo
Drug Discovery Today,
Год журнала:
2024,
Номер
29(3), С. 103907 - 103907
Опубликована: Янв. 30, 2024
The
development
of
protein
kinase
inhibitors
(PKIs)
has
gained
significance
owing
to
their
therapeutic
potential
for
diseases
like
cancer.
In
addition,
there
been
a
rise
in
refining
activity
assays,
each
possessing
unique
biological
and
analytical
characteristics
crucial
PKI
development.
However,
the
pipeline
experiences
high
attrition
rates
approved
PKIs
exhibit
unexploited
because
variable
patient
responses.
Enhancing
efficiency
involves
addressing
challenges
related
understanding
mechanism
action
employing
biomarkers
precision
medicine.
Selecting
appropriate
assays
these
can
overcome
rate
issues.
This
review
delves
into
current
obstacles
inhibitor
elucidates
that
provide
solutions.
Teaser:
Kinase
hold
accelerate
effective
by
multitude
challenges.
Here,
we
explore
how
solve
improve