| The epidermal
growth factor receptor (EGFR) has been shown to
be expressed at a relatively high level in non-small
cell lung cancer (NSCLC), and it provides an important
target for lung cancer therapy. Blockade of the
EGFR by small molecule inhibitors of the tyrosine
kinase (TK), such as gefitinib and erlotinib,
have shown some limited clinical utility against
NSCLC, but response rates have been restricted
for the most part to patients having EGFR mutations.
We have evidence that another ligand receptor
system, the gastrin releasing peptide receptor
(GRPR) pathway, can activate similar cell signals
in NSCLC that are also activated by EGFR, due
to the release of EGFR ligands such as TGF-? and
amphiregulin. The EGFR ligand release appears
to induce cell proliferation and protects the
cells from the cell-killing effects of EGFR inhibitors.
Previous work from our laboratory has shown that
expression of GRPR is associated with an increased
risk for lung cancer particularly in female non-smokers.
The GRPR gene is located on the X-chromosome and
escapes X-chromosome inactivation. This occurs
only in females, giving further evidence that
GRPR may play a role in the increased susceptibility
of women to lung cancer by promoting the release
of EGFR ligands. Published work from our laboratory
has also shown that GRP inhibition in vitro using
GRP antagonists can increase the therapeutic effects
of gefitinib in NSCLC. Modulation of the GRPR
pathway might alter lung tumor growth, especially
in BAC or adenocarcinoma with BAC features, which
are found predominantly in female patients. In
order to evaluate the role of GRPR in lung tumor
carcinogenesis and to test the chemotherapeutic
potential of combined inhibition of the GRPR and
the EGFR pathways, we have made a transgenic mouse
that overexpresses the human GRPR gene in the
small airway epithelium. Preliminary data have
shown that the GRPR-overexpressing mice develop
small airway hyperplasia compared to their wild-type
littermates, and that they are more susceptible
to lung cancer when treated with a tobacco carcinogen,
nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
(NNK). We will use this in vivo model to determine
the susceptibility to lung carcinogenesis and
the status of GRPR/EGFR downstream signaling molecules
in the transgenic mice expressing the human GRPR
gene.
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