Potential drug targets for prostate cancer ： A mendelian randomization study and application for target-derived drug design
Abstract
Background
The
advent
of
targeted
cancer
therapies
has
led
to
a
decline
in
prostate
(PCa)
incidence
and
mortality
rates.
Nevertheless,
challenges
persist
due
the
long-term
single-agent
therapeutic
insensitivity
resistance
encountered
PCa
treatment.
Therefore,
there
is
an
urgent
need
for
novel
drug
targets
address
these
therapy.
Method
We
analyzed
731
plasma
proteins
summary
GWAS
data
from
Prostate
Cancer
Association
Group
investigate
associated
genomic
alterations
(control:
case
=
61
106:
79
148 ).
Cis-acting
Mendelian
randomization
Bayesian
analysis
was
applied
reveal
causality
between
protein
PCa.
Additionally,
protein-protein
interaction
(PPI)
performed
discover
potential
coactions
identified
target
established
approved
by
FDA
treatment
Furthermore,
we
utilized
Alpha
Fold
2
predict
3D
complex
structure
targets.
Finally,
findings
were
validated
using
UK
Biobank
European
Bioinfomatics
Institute,
six
promising
categorized
into
three
tiers.
Results
Six
causal
including
MSMB,
IGF2R,
KDELC2,
TNFRSF10B,
GSTP1,
SPINT2
discovered
through
analysis.
Among
them,
MSMB
(Odds
ratio
(OR)
0.81;
95%
confidence
interval
(CI)
:
0.80–0.82;
P
2.52×10−
148),
IGF2R
(OR
0.92;
CI:
0.90–0.94;
4.57×10−
10),
KDELC2
0.89;
0.86–0.93;
1.89×10−
8),
TNFRSF10B
0.74;
0.65–0.83;
2.41×10−
7),
GSTP1
0.82;
0.75–0.90;
4.22×10−
5)
inversely
with
risk,
upregulate
level
1.05;
1.03–1.05;
1.49×10−
6)
increased
risk.
None
had
reverse
causality.
shared
same
variant
co-localization
(PPH4
>
0.8).
During
external
validation,
five
replicated
at
least
one
dataset
except
IGF2R.
Conclusions
Our
study
highlighted
that
constellation
have
been
as
PCa,
which
might
provide
valuable
insights
rational
design
drugs
Research Square (Research Square), Год журнала: 2024, Номер unknown
Опубликована: Сен. 2, 2024
Язык: Английский