| Of considerable
recent interest in the field of lung cancer has
been the finding of mutations in the tyrosine
kinase domain of EGFR in patients who have responded
to gefitinib or erlotinib. Nearly 20% of NSCLC
harbor EGFR mutations and these mutations were
more frequent in never smokers than ever smokers
and in females versus males. Importantly, mutant
EGFR selectively activate Akt and STAT pathways
that are important in NSCLC cell survival suggesting
that the anti-tumor effects of EGFR inhibitors
is mediated in part through inhibition of essential
downstream survival signaling pathways such as
STATs and Akt. A key pathway downstream of EGFR
is Stat3, a member of the Signal Transducers and
Activators of Transcription (STAT) family of transcription
factors. Stat3 regulates a number of pathways
important in tumorigenesis including cell cycle
progression, apoptosis, tumor angiogenesis, invasion
and metastasis, and tumor cell evasion of the
immune system. Our laboratory previously reported
that inhibition of Stat3, either directly or indirectly
with SRC inhibitors, results in apoptosis in NSCLC
cell lines without EGFR mutations. In follow up
studies, we investigated genome-wide changes in
gene expression in lung cancer cells and identified
a number of both known Stat3 targets as well as
novel Stat3 target genes/pathways implicated in
the “hallmarks of cancer”. We have
identified nuclear pStat3 expression in 54% of
tumors that was correlated with limited smoking
history and a trend towards higher pStat3 expression
in adenocarcinomas compared with other tumor histology.
Importantly, we found a strong positive correlation
between pEGFR and pStat3 expression and an inverse
correlation between pStat3 and apoptosis consistent
with less apoptosis in tumors expressing high
amounts of pStat3. Finally, we have found that
cell lines with mutant EGFR have increased levels
of activated Stat3 compared to cell lines without
mutant EGFR and these cells have enhanced sensitivity
to novel small molecule inhibitors of EGFR and
SRC. Given the high level of Stat3 activity in
NSCLC with EGFR mutations and the importance of
Stat3 in oncogenesis, we hypothesize that Stat3
is an excellent molecular target in this subset
of NSCLC. Direct or indirect targeting of Stat3
may have potent anti-tumor effects and may be
used on combination therapy along with other agents
targeting survival signaling pathways in NSCLC.
We postulate that this important survival cascade
can be inhibited by novel SRC inhibitors that
interrupt signaling between mutant EGFR and Stat3.
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