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Src Mutation Induces Acquired Lapatinib Resistance in ERBB2-Amplified Human Gastroesophageal Adenocarcinoma Models.
[esophageal adenocarcinoma]
ERBB
2
-
directed
therapy
is
now
a
routine
component
of
therapy
for
ERBB
2
-
amplified
metastatic
gastroesophageal
adenocarcinomas
.
However
,
there
is
little
knowledge
of
the
mechanisms
by
which
these
tumors
develop
acquired
resistance
to
ERBB
2
inhibition
.
To
investigate
this
question
we
sought
to
characterize
cell
line
models
of
ERBB
2
-
amplified
gastroesophageal
adenocarcinoma
with
acquired
resistance
to
ERBB
2
inhibition
.
We
generated
lapatinib-resistant
(
LR
)
subclones
from
an
initially
lapatinib-sensitive
ERBB
2
-
amplified
esophageal
adenocarcinoma
cell
line
,
OE
19
.
We
subsequently
performed
genomic
characterization
and
functional
analyses
of
resistant
subclones
with
acquired
lapatinib
resistance
.
We
identified
a
novel
,
acquired
SrcE
527
K
mutation
in
a
subset
of
LR
OE
19
subclones
.
Cells
with
this
mutant
allele
harbour
increased
Src
phosphorylation
.
Genetic
and
pharmacologic
inhibition
of
Src
resensitized
these
subclones
to
lapatinib
.
Biochemically
,
Src
mutations
could
activate
both
the
phosphatidylinositol
3
-
kinase
and
mitogen
activated
protein
kinase
pathways
in
the
lapatinib-treated
LR
OE
19
cells
.
Ectopic
expression
of
Src
E
527
K
mutation
also
was
sufficient
to
induce
lapatinib
resistance
in
drug-naïve
cells
.
These
results
indicate
that
pathologic
activation
of
Src
is
a
potential
mechanism
of
acquired
resistance
to
ERBB
2
inhibition
in
ERBB
2
-
amplified
gastroesophageal
cancer
.
Although
Src
mutation
has
not
been
described
in
primary
tumor
samples
,
we
propose
that
the
Src
hyperactivation
should
be
investigated
in
the
settings
of
acquired
resistance
to
ERBB
2
inhibition
in
esophageal
and
gastric
adenocarcinoma
.