Cancers,
Год журнала:
2024,
Номер
16(24), С. 4239 - 4239
Опубликована: Дек. 19, 2024
Among
solid
tumors,
cholangiocarcinoma
(CCA)
emerges
as
one
of
the
most
difficult
to
eradicate.
The
silent
and
asymptomatic
nature
this
tumor,
particularly
in
its
early
stages,
well
high
heterogeneity
at
genomic,
epigenetic,
molecular
levels
delay
diagnosis,
significantly
compromising
efficacy
current
therapeutic
options
thus
contributing
a
dismal
prognosis.
Extensive
research
has
been
conducted
on
pathobiology
CCA,
recent
advances
have
made
classification
characterization
new
targets.
Both
targeted
therapy
immunotherapy
emerged
effective
safe
strategies
for
various
types
cancers,
demonstrating
potential
benefits
advanced
CCA.
Furthermore,
deeper
comprehension
cellular
components
tumor
microenvironment
(TME)
opened
up
possibilities
innovative
treatment
methods.
This
review
discusses
evidence
biology
highlighting
novel
possible
druggable
Clinical Cancer Research,
Год журнала:
2024,
Номер
30(21), С. 4943 - 4956
Опубликована: Сен. 3, 2024
Abstract
Purpose:
Understanding
resistance
to
selective
FGFR
inhibitors
is
crucial
improve
the
clinical
outcomes
of
patients
with
FGFR2-driven
malignancies.
Experimental
Design:
We
analyzed
sequential
ctDNA,
±
whole-exome
sequencing,
or
targeted
next-generation
sequencing
on
tissue
biopsies
from
tumors
harboring
activating
FGFR2
alterations
progressing
pan-FGFR–selective
inhibitors,
collected
in
prospective
UNLOCK
program.
FGFR2::BICC1
Ba/F3
and
patient-derived
xenograft
models
were
used
for
functional
studies.
Results:
Thirty-six
included.
In
cholangiocarcinoma,
at
both
reversible
(e.g.,
pemigatinib
erdafitinib)
irreversible
inhibitor
futibatinib,
polyclonal
kinase
domain
mutations
frequent
(14/27
patients).
Tumors
other
than
cholangiocarcinoma
shared
same
mutated
residues,
but
polyclonality
was
rare
(1/9
At
14
residues
mutated—after
only
molecular
brake
N550
gatekeeper
V565.
Off-target
PI3K/mTOR
MAPK
pathways
found
11
patients,
often
together
on-target
mutations.
progression
a
first
inhibitor,
12
received
futibatinib
lirafugratinib
(irreversible
inhibitors),
variable
depending
previous
mechanisms.
Two
TSC1
PIK3CA
benefited
everolimus.
cell
viability
assays
pharmacologic
studies
xenografts,
retained
better
activity
against
mutations,
active
recalcitrant
V565L/F/Y.
Conclusions:
malignancies
are
characterized
by
high
intra-
interpatient
heterogeneity,
particularly
cholangiocarcinoma.
Resistance
can
be
overcome
sequential,
molecularly
oriented
treatment
strategies
across
tumors.
Journal of Hematology & Oncology,
Год журнала:
2024,
Номер
17(1)
Опубликована: Ноя. 9, 2024
Variants
in
the
RAS
family
(HRAS,
NRAS
and
KRAS)
are
among
most
common
mutations
found
cancer.
About
19%
patients
with
cancer
harbor
mutations,
which
typically
associated
poor
clinical
outcomes.
Over
past
four
decades,
KRAS
has
long
been
considered
an
undruggable
target
due
to
absence
of
suitable
small-molecule
binding
sites
within
its
mutant
isoforms.
However,
recent
advancements
drug
design
have
made
RAS-targeting
therapies
viable,
particularly
approval
direct
Frontiers in Oncology,
Год журнала:
2025,
Номер
15
Опубликована: Апрель 7, 2025
FGFR2
fusions
occur
in
up
to
14%
of
patients
with
intrahepatic
cholangiocarcinoma
(iCCA)
and
have
been
considered
as
therapeutic
target
for
FGFR
inhibitors
(FGFRi).
However,
response
targeted
treatment
may
be
limited
due
the
emergence
various
resistance
mechanisms.
We
report
a
case
recurrent
iCCA
43-year-old
patient
fusion,
who
was
treated
Lenvatinib.
Next-generation
sequencing
(NGS)
tumor-normal
DNA
tumor
RNA
under
Lenvatinib
confirmed
however
no
further
molecular
mutation
observed.
After
failure
FGFRi
(Lenvatinib
Infigratinib)
ten
months
later,
repeated
NGS
analysis
revealed
new
gain-of-function
PIK3CA
homozygous
deletion
CDKN2A/B,
potentially
representing
an
acquired
mechanism.
The
emerging
inhibitor
has
implications
subsequent
strategies.
International Journal of Molecular Sciences,
Год журнала:
2025,
Номер
26(9), С. 4393 - 4393
Опубликована: Май 6, 2025
Immune
checkpoint
inhibitors
have
become
a
mainstay
of
treatment
in
many
solid
organ
malignancies.
Alongside
this
has
been
the
rapid
development
identification
and
targeting
oncogenic
drivers.
The
presence
alterations
drivers
not
only
predicts
response
to
target
therapy
but
can
modulate
immune
microenvironment
influence
immunotherapy.
Combining
with
targeted
agents
is
an
attractive
therapeutic
option
overlapping
toxicity
profiles
may
limit
clinical
use
some
combinations.
In
addition,
there
growing
evidence
shared
resistance
mechanisms
that
alter
immunotherapy
when
it
used
after
therapy.
Understanding
complex
interaction
between
drivers,
vital
for
selecting
right
treatment,
at
time
patient.
review,
we
summarise
preclinical
four
common
on
inhibitor
response,
combination
therapies,
mechanisms.
We
highlight
need
more
randomised
trials
investigating
both
sequential
