| Targeting proteins
on the cell surface, called epidermal growth factor
receptors (EGFR), is an effective therapy for
a subset of lifelong non-smokers who develop lung
cancer. Lifelong non-smokers who develop lung
cancer have been found to have mutations or alterations
in EGFR that results in exquisite sensitivity
to drugs such as gefitinib or erlotinib. Unfortunately,
while tumor shrinkage can last for one to two
years, the tumor cells ultimately become resistant
to these drugs resulting in regrowth of the tumor
and death of the patient. Our laboratory has been
interested in an important set of signaling proteins
downstream of EGFR called STAT proteins. These
proteins act to communicate signals from EGFR
to important genes that control cell growth, cell
survival, cell metastasis (spreading), and angiogenesis
(new blood vessel formation). We previously demonstrated
that eliminating the function of Stat3 results
in lung cancer cell death. In addition, our previous
work showed that a protein called SRC is important
in maintaining Stat3 activity. Our more recent
unpublished data shows that lung cancer cells
with EGFR mutations have enhanced Stat3 activity.
In addition, early experiments with new drugs
that inhibit SRC show that these drugs can kill
lung cancer cells with EGFR mutations. It is our
hypothesis that SRC and Stat3 proteins are ideal
targets for cancer therapy in lifelong non-smokers
who develop lung cancer resulting from EGFR mutations.
We plan a series of experiments using mutant EGFR
cell lines to demonstrate that inhibitors of SRC
and/or Stat3 can kill these cancer cells and may
have additive effect when used in conjunction
with EGFR inhibitors such as gefitinib or erlotinib.
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