bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2024,
Volume and Issue:
unknown
Published: Nov. 15, 2024
Abstract
Trastuzumab
resistance
remains
a
challenge
for
HER2
positive
breast
cancer
treatment.
Targeting
metabolic
reprogramming
would
provide
novel
insights
therapeutic
strategies.
Here,
we
integrated
metabolomics,
transcriptomics
and
epigenomics
data
of
trastuzumab
sensitive
primary
resistant
to
identify
alterations.
Aberrant
cysteine
metabolism
was
discovered
in
at
both
circulating
intracellular
levels.
The
inhibition
SLC7A11
starvation
could
synergize
with
induce
ferroptosis.
Mechanistically,
increased
H3K4me3
decreased
DNA
methylation
enhanced
transcription
cystine
uptake
cancer.
regulation
epigenetic
modifications
modulated
ferroptosis
sensitivity.
These
results
revealed
an
innovative
approach
overcoming
by
targeting
specific
amino
acid
metabolism.
Pharmacological Research,
Journal Year:
2024,
Volume and Issue:
204, P. 107205 - 107205
Published: May 6, 2024
Triple-negative
breast
cancer
(TNBC)
is
an
aggressive
subtype
lacking
estrogen
receptors,
progesterone
receptors
and
lacks
HER2
overexpression.
This
absence
of
critical
molecular
targets
poses
significant
challenges
for
conventional
therapies.
Immunotherapy,
remarkably
immune
checkpoint
blockade,
offers
promise
TNBC
treatment,
but
its
efficacy
remains
limited.
Epigenetic
dysregulation,
including
altered
DNA
methylation,
histone
modifications,
imbalances
in
regulators
such
as
BET
proteins,
plays
a
crucial
role
development
resistance
to
treatment.
Hypermethylation
tumor
suppressor
gene
promoters
the
imbalance
methyltransferases
EZH2
deacetylases
(HDACs)
profoundly
influence
cell
proliferation,
survival,
metastasis.
In
addition,
epigenetic
alterations
critically
shape
microenvironment
(TME),
composition,
cytokine
signaling,
expression,
ultimately
contributing
evasion.
Targeting
these
mechanisms
with
specific
inhibitors
HDAC
combination
immunotherapy
represents
compelling
strategy
remodel
TME,
potentially
overcoming
evasion
enhancing
therapeutic
outcomes
TNBC.
review
aims
comprehensively
elucidate
current
understanding
modulation
TNBC,
on
potential
combining
therapies
overcome
posed
by
this
subtype.
Advanced Science,
Journal Year:
2024,
Volume and Issue:
11(18)
Published: March 9, 2024
Abstract
Secondary
trastuzumab
resistance
represents
an
evolutionary
adaptation
of
HER2‐positive
breast
cancer
during
anti‐HER2
treatment.
Most
current
studies
have
tended
to
prioritize
HER2
and
its
associated
signaling
pathways,
often
overlooking
broader
but
seemingly
less
relevant
cellular
processes,
along
with
their
genetic
epigenetic
mechanisms.
Here,
transcriptome
data
is
not
only
characterized
also
examined
epigenomic
3D
genome
architecture
information
in
both
trastuzumab‐sensitive
secondary‐resistant
cells.
The
findings
reveal
that
the
global
metabolic
reprogramming
may
stem
from
genome‐wide
alterations
histone
modifications
chromatin
structure.
Specifically,
transcriptional
activities
key
genes
involved
lipid
metabolism
appear
be
regulated
by
variant
promoter
H3K27me3
H3K4me3
modifications,
as
well
promoter‐enhancer
interactions.
These
discoveries
offer
valuable
insights
into
how
cells
adapt
anti‐tumor
drugs
potential
impact
future
diagnostic
treatment
strategies.
Molecular Cancer,
Journal Year:
2025,
Volume and Issue:
24(1)
Published: March 8, 2025
Epigenomic
modifications—such
as
DNA
methylation,
histone
acetylation,
and
methylation—and
their
implications
in
tumorigenesis,
progression,
treatment
have
emerged
a
pivotal
field
cancer
research.
Tumors
undergo
metabolic
reprogramming
to
sustain
proliferation
metastasis
nutrient-deficient
conditions,
while
suppressing
anti-tumor
immunity
the
tumor
microenvironment
(TME).
Concurrently,
immune
cells
within
immunosuppressive
TME
adaptations,
leading
alterations
function.
The
complicated
interplay
between
metabolites
epigenomic
modulation
has
spotlighted
significance
of
regulation
immunometabolism.
In
this
review,
characteristics
modification
associated
with
tumors
are
systematically
summarized
alongside
regulatory
roles
Classical
emerging
approaches
delineated
broaden
boundaries
research
on
crosstalk
immunometabolism
epigenomics.
Furthermore,
we
discuss
potential
therapeutic
strategies
that
target
modulate
modifications,
highlighting
burgeoning
synergy
therapies
immunotherapy
promising
avenue
for
treatment.
Seminars in Cancer Biology,
Journal Year:
2024,
Volume and Issue:
unknown
Published: Dec. 1, 2024
Elevated
lipid
metabolism
is
one
of
hallmarks
malignant
tumors.
Lipids
not
only
serve
as
essential
structural
components
biological
membranes
but
also
provide
energy
and
substrates
for
the
proliferation
cancer
cells
tumor
growth.
Cancer
meet
their
needs
by
coordinating
processes
absorption,
synthesis,
transport,
storage,
catabolism.
As
research
in
this
area
continues
to
deepen,
numerous
new
discoveries
have
emerged,
making
it
crucial
scientists
stay
informed
about
developments
metabolism.
In
review,
we
first
discuss
relevant
concepts
theories
or
assumptions
that
help
us
understand
-based
therapies.
We
then
systematically
summarize
latest
advancements
including
mechanisms,
novel
targets,
up-to-date
pre-clinical
clinical
investigations
anti-cancer
treatment
with
targeted
drugs.
Finally,
emphasize
emerging
directions
therapeutic
strategies,
future
prospective
challenges.
This
review
aims
insights
guidance
field
Trastuzumab
resistance
remains
a
challenge
for
HER2
positive
breast
cancer
treatment.
Targeting
metabolic
reprogramming
would
provide
novel
insights
therapeutic
strategies.
Here,
we
integrated
metabolomics,
transcriptomics
and
epigenomics
data
of
trastuzumab
sensitive
primary
resistant
to
identify
alterations.
Aberrant
cysteine
metabolism
was
discovered
in
at
both
circulating
intracellular
levels.
The
inhibition
SLC7A11
starvation
could
synergize
with
induce
ferroptosis.
Mechanistically,
increased
H3K4me3
decreased
DNA
methylation
enhanced
transcription
cystine
uptake
cancer.
regulation
epigenetic
modifications
modulated
ferroptosis
sensitivity.
These
results
revealed
an
innovative
approach
overcoming
by
targeting
specific
amino
acid
metabolism.
Trastuzumab
resistance
remains
a
challenge
for
HER2
positive
breast
cancer
treatment.
Targeting
metabolic
reprogramming
would
provide
novel
insights
therapeutic
strategies.
Here,
we
integrated
metabolomics,
transcriptomics
and
epigenomics
data
of
trastuzumab
sensitive
primary
resistant
to
identify
alterations.
Aberrant
cysteine
metabolism
was
discovered
in
at
both
circulating
intracellular
levels.
The
inhibition
SLC7A11
starvation
could
synergize
with
induce
ferroptosis.
Mechanistically,
increased
H3K4me3
decreased
DNA
methylation
enhanced
transcription
cystine
uptake
cancer.
regulation
epigenetic
modifications
modulated
ferroptosis
sensitivity.
These
results
revealed
an
innovative
approach
overcoming
by
targeting
specific
amino
acid
metabolism.
Trastuzumab
resistance
remains
a
challenge
for
HER2
positive
breast
cancer
treatment.
Targeting
metabolic
reprogramming
would
provide
novel
insights
therapeutic
strategies.
Here,
we
integrated
metabolomics,
transcriptomics
and
epigenomics
data
of
trastuzumab
sensitive
primary
resistant
to
identify
alterations.
Aberrant
cysteine
metabolism
was
discovered
in
at
both
circulating
intracellular
levels.
The
inhibition
SLC7A11
starvation
could
synergize
with
induce
ferroptosis.
Mechanistically,
increased
H3K4me3
decreased
DNA
methylation
enhanced
transcription
cystine
uptake
cancer.
regulation
epigenetic
modifications
modulated
ferroptosis
sensitivity.
These
results
revealed
an
innovative
approach
overcoming
by
targeting
specific
amino
acid
metabolism.
Nature Communications,
Journal Year:
2025,
Volume and Issue:
16(1)
Published: April 25, 2025
Anti-HER2
antibodies
are
effective
but
often
lead
to
resistance
in
patients
with
HER2+
breast
cancer.
Here,
we
report
an
epigenetic
crosstalk
aberrant
glycerophospholipid
metabolism
and
inflammation
as
a
key
mechanism
of
anti-HER2
therapies
Histone
reader
ZMYND8
specifically
confers
cancer
cells
against
trastuzumab
and/or
pertuzumab.
Mechanistically,
enhances
cPLA2α
expression
resistant
tumor
through
inducing
c-Myc.
inactivates
phosphatidylcholine-specific
phospholipase
C
inhibit
phosphatidylcholine
breakdown
into
diacylglycerol,
which
diminishes
protein
kinase
activity
leading
interleukin-27
secretion.
Supplementation
counteracts
loss
reinforce
patient-derived
organoids.
Upregulation
ZMYND8,
c-Myc,
cPLA2α,
IL-27
is
prevalent
following
HER2-targeted
therapies.
Targeting
c-Myc
or
effectively
overcomes
therapy
xenografts.
Collectively,
this
study
uncovers
druggable
signaling
cascade
that
drives
Signal Transduction and Targeted Therapy,
Journal Year:
2025,
Volume and Issue:
10(1)
Published: Feb. 14, 2025
Abstract
Aberrant
RNA
alternative
splicing
in
cancer
generates
varied
novel
isoforms
and
protein
variants
that
facilitate
progression.
Here,
we
employed
the
advanced
long-read
full-length
transcriptome
sequencing
on
gallbladder
normal
tissues,
tumors,
cell
lines
to
establish
a
comprehensive
transcriptomic
atlas.
It
is
of
note
receptor
tyrosine
kinases
were
one
most
dynamic
components
with
highly
variable
transcript,
Erb-B2
kinase
2
(ERBB2)
as
prime
representative.
A
designated
ERBB2
i14e,
was
identified
for
encoding
functional
protein,
its
expression
elevated
strongly
associated
worse
prognosis.
With
regulation
factors
ESRP1/2,
i14e
alternatively
spliced
from
intron
14
encoded
peptide
proved
interaction
ERBB3
downstream
signaling
activation
AKT.
inducible
attenuated
anti-ERBB2
treatment
efficacy
tumor
xenografts.
Further
studies
patient
derived
xenografts
models
validated
blockage
antisense
oligonucleotide
enhanced
sensitivity
trastuzumab
drug
conjugates.
Overall,
this
study
provides
specific
profile
discovers
mechanism
resistance,
thus
ultimately
devising
strategies
improve
therapy.
