Frontiers in Immunology,
Год журнала:
2023,
Номер
14
Опубликована: Март 10, 2023
The
development
and
growth
of
tumors
remains
an
important
ongoing
threat
to
human
life
around
the
world.
While
advanced
therapeutic
strategies
such
as
immune
checkpoint
therapy
CAR-T
have
achieved
astonishing
progress
in
treatment
both
solid
hematological
malignancies,
malignant
initiation
progression
cancer
a
controversial
issue,
further
research
is
urgently
required.
experimental
animal
model
not
only
has
great
advantages
simulating
occurrence,
development,
transformation
mechanisms
tumors,
but
also
can
be
used
evaluate
effects
diverse
array
clinical
interventions,
gradually
becoming
indispensable
method
for
research.
In
this
paper,
we
reviewed
recent
relation
mouse
rat
models,
focusing
on
spontaneous,
induced,
transgenic,
transplantable
tumor
help
guide
future
study
prevention.
Cell,
Год журнала:
2023,
Номер
186(8), С. 1729 - 1754
Опубликована: Апрель 1, 2023
Pancreatic
ductal
adenocarcinoma
(PDAC)
remains
one
of
the
deadliest
cancers.
Significant
efforts
have
largely
defined
major
genetic
factors
driving
PDAC
pathogenesis
and
progression.
tumors
are
characterized
by
a
complex
microenvironment
that
orchestrates
metabolic
alterations
supports
milieu
interactions
among
various
cell
types
within
this
niche.
In
review,
we
highlight
foundational
studies
driven
our
understanding
these
processes.
We
further
discuss
recent
technological
advances
continue
to
expand
complexity.
posit
clinical
translation
research
endeavors
will
enhance
currently
dismal
survival
rate
recalcitrant
disease.
Nature,
Год журнала:
2023,
Номер
619(7968), С. 160 - 166
Опубликована: Май 31, 2023
KRAS
is
one
of
the
most
commonly
mutated
proteins
in
cancer,
and
efforts
to
directly
inhibit
its
function
have
been
continuing
for
decades.
The
successful
these
has
development
covalent
allele-specific
inhibitors
that
trap
G12C
inactive
conformation
suppress
tumour
growth
patients1-7.
Whether
inactive-state
selective
inhibition
can
be
used
therapeutically
target
non-G12C
mutants
remains
under
investigation.
Here
we
report
discovery
characterization
a
non-covalent
inhibitor
binds
preferentially
with
high
affinity
state
while
sparing
NRAS
HRAS.
Although
limited
only
few
amino
acids,
evolutionary
divergence
GTPase
domain
RAS
isoforms
was
sufficient
impart
orthosteric
allosteric
constraints
selectivity.
blocked
nucleotide
exchange
prevent
activation
wild-type
broad
range
mutants,
including
G12A/C/D/F/V/S,
G13C/D,
V14I,
L19F,
Q22K,
D33E,
Q61H,
K117N
A146V/T.
Inhibition
downstream
signalling
proliferation
restricted
cancer
cells
harbouring
mutant
KRAS,
drug
treatment
suppressed
mice,
without
having
detrimental
effect
on
animal
weight.
Our
study
suggests
oncoproteins
cycle
between
an
active
are
dependent
activation.
Pan-KRAS
inhibitors,
such
as
described
here,
therapeutic
implications
merit
clinical
investigation
patients
KRAS-driven
cancers.
Cancer Discovery,
Год журнала:
2022,
Номер
12(4), С. 924 - 937
Опубликована: Янв. 19, 2022
KRAS
is
the
most
frequently
mutated
oncogene,
harboring
mutations
in
approximately
one
seven
cancers.
Allele-specific
KRASG12C
inhibitors
are
currently
changing
treatment
paradigm
for
patients
with
KRASG12C-mutated
non-small
cell
lung
cancer
and
colorectal
cancer.
The
success
of
addressing
a
previously
elusive
allele
has
fueled
drug
discovery
efforts
all
mutants.
Pan-KRAS
drugs
have
potential
to
address
broad
patient
populations,
including
KRASG12D-,
KRASG12V-,
KRASG13D-,
KRASG12R-,
KRASG12A-mutant
or
wild-type-amplified
cancers,
as
well
cancers
acquired
resistance
inhibitors.
Here,
we
review
actively
pursued
allele-specific
pan-KRAS
inhibition
strategies
their
utility.
Mutant-selective
target
fraction
(approximately
13.6%)
KRAS-driven
A
arsenal
needed
comprehensively
conquer
Conceptually,
foresee
two
future
classes
medicines:
mutant-selective
targeting
individual
variant
alleles
therapeutics
range
alterations.
Abstract
Kirsten
Rat
Sarcoma
Viral
Oncogene
Homolog
(KRAS)
is
the
most
frequently
mutated
oncogene,
occurring
in
a
variety
of
tumor
types.
Targeting
KRAS
mutations
with
drugs
challenging
because
considered
undruggable
due
to
lack
classic
drug
binding
sites.
Over
past
40
years,
great
efforts
have
been
made
explore
routes
for
indirect
targeting
mutant
cancers,
including
expression,
processing,
upstream
regulators,
or
downstream
effectors.
With
advent
(G12C)
inhibitors,
are
now
druggable.
Despite
such
inhibitors
showing
remarkable
clinical
responses,
resistance
monotherapy
eventually
developed.
Significant
progress
has
understanding
mechanisms
KRAS-mutant
inhibitors.
Here
we
review
recent
advances
therapeutic
approaches
and
discuss
opportunities
combination
therapy.
Journal of Hematology & Oncology,
Год журнала:
2022,
Номер
15(1)
Опубликована: Окт. 25, 2022
Abstract
After
decades
of
efforts,
we
have
recently
made
progress
into
targeting
KRAS
mutations
in
several
malignancies.
Known
as
the
‘holy
grail’
targeted
cancer
therapies,
is
most
frequently
mutated
oncogene
human
Under
normal
conditions,
shuttles
between
GDP-bound
‘off’
state
and
GTP-bound
‘on’
state.
Mutant
constitutively
activated
leads
to
persistent
downstream
signaling
oncogenesis.
In
2013,
improved
understanding
biology
newer
drug
designing
technologies
led
crucial
discovery
a
cysteine
drug-binding
pocket
mutant
G12C
protein.
Covalent
inhibitors
that
block
were
successfully
developed
sotorasib
was
first
inhibitor
be
approved,
with
more
pipeline.
Simultaneously,
effects
on
tumour
microenvironment
also
discovered,
partly
owing
universal
use
immune
checkpoint
inhibitors.
this
review,
discuss
discovery,
biology,
function
We
relationship
microenvironment,
therapeutic
strategies
target
KRAS.
Finally,
review
current
clinical
evidence
ongoing
trials
novel
agents
shine
light
resistance
pathways
known
so
far.
