Tumor suppressor genes 3

Receptor tyrosine kinases
The EGFR family
The EGFR family of receptors are transmembrane
TK receptors and are composed of EGFR, HER2,
HER3, and HER4 and each has unique proper-
ties. For example, HER2 lacks a functional ligand-
binding domain and HER3 lacks kinase activity [63].
Upon ligand binding, these EGFR family members
form active homo- and hetero-dimers, leading to
autophosphorylation and activation of intracellular
signaling cascades. EGFR is overexpressed in ∼70%
ofNSCLCs but rarely expressed in SCLCs [64]. There
are several drugs targeting EGFR or HER2 currently
available including the small molecule TKIs, gefi-
tinib, erlotinib, and the monoclonal antibodies, ce-
tuximab (targeting EGFR), and trastuzumab (target-
ing HER2).
Recently, several mutations in the TK domain of
EGFR have been described, and are not infrequent in
NSCLC (10–20%), but never occur in SCLC [65,66].
Of interest is that TK domain mutations are almost
exclusive to lung cancer, whereas intracellular re-
gion mutations are found in glioblastomas. In lung
cancer, these mutations are limited to the first four
exons of the TK domain and are categorized into
three different types (deletions, insertions, and mis-
sense point mutations). Inframe deletions in exon19 (44% of all mutations) and missense mutations
in exon 21 (41% of all mutations) are the most fre-
quent, accounting for more than 80% of all muta-
tions [67]. Importantly, the presence of mutations
in TK domain correlates with the drug sensitivity to
TKIs [65,66]. An intriguing characteristic of EGFR
mutations is that they occur in a highly selected
subpopulation: female East-Asian never smokers
with adenocarcinoma histology [68]. Notably, be-
fore EGFR mutations were discovered, all of same
clinicopathological factors were found to be associ-
ated with tumor responses to TKIs [69,70].
Although several studies have confirmed the re-
lationship between the presence of mutant EGFR
and the response to TKIs [65,66,71], a subset of
NSCLC patients with mutant EGFRs do not respond
to TKIs. These tumors often (>50%) have a “sec-
ond” TK domain mutation (T790M) usually found
in patientswho relapse after TKI treatment, suggest-
ing its contribution to acquired resistance to TKIs
[72,73]. However, several examples of the T790M
mutations occur in lung tumors not treated with
EGFR TKIs, and often themutation is only in a small
subset of the tumor cells. This contrasts with the
other EGFR TK domain mutations, which are in all
tumor cells.Also, a germline EGFR T790Mmutation
was reported to be associated with familial NSCLC,
suggesting that this mutation could predispose peo-
ple to lung cancer [74]. Fortunately, there are EGFR
TKIs that inhibit EGFR with the T790M mutation,
and these drugs are currently under clinical evalu-
ation [75].
Some patients without EGFR mutation also re-
spond to TKIs, and several predictive markers other
than EGFR mutation have been reported to corre-
late with TKI response, including EGFR amplifica-
tion, elevated EGFR protein, HER2 amplification,
HER3 amplification, and activation of AKT [76–
80]. In fact, KRAS mutations and EGFR mutations
are mutually exclusive. KRAS mutations are asso-
ciated with cigarette smoking, while EGFR muta-
tions generally occur in never smokers [81]. These
studies suggest that other biological features be-
sides EGFRmutation status determine TKI response.
Among biologic predictors, EGFR mutation and
amplification by fluorescence in situ hybridization
are highly correlated with TKI response whileEGFR protein expression gives conflicting results
[65,66,71,76,82]. There is also the possibility that
tumors with EGFR mutations are associated with
better survival independent of TKI treatment. Thus,
all survival studies after TKI treatment need to have
molecular analyses for comparison [80,83,84]. Two
well-controlled phase III studies were conducted for
these drugs. The results of these studies showed that
erlotinib prolonged survival of previously treated
NSCLC patients by 2 months (BR21 trial), while
gefitinib failed to show survival benefit (Iressa Sur-
vival Evalulation in Lung Cancer (ISEL)) [86,87].
Despite positive preclinical studies of the combi-
nation of TKI and chemotherapy, several phase
III studies have failed to show a survival bene-
fit of adding erlotinib or gefitinib to conventional
chemotherapy [88,89]. Finally, lung cancers with
EGFR mutations are more sensitive to ionizing ra-
diation than those without EGFR mutations, which
potentially provides a molecular basis for combined
modality treatment involving TKIs and radiother-
apy [90].
While standard criteria for selecting patients with
NSCLC for TKI therapy are being developed, in prac-
tice, East-Asian female patients with tumors that
have EGFR mutations or EGFR amplification and
that are never smokers often receive TKI therapy. To
address this issue, prospective clinical trials designed
to incorporate the patient’s clinicopathological data
as well as molecular biological features (EGFR mu-
tation and/or amplification) of the tumors are cur-
rently underway.
HER2 mutations occur in 2% of NSCLCs. All re-
ported HER2 mutations are in-frame insertions in
exon 20 and target the corresponding TK domain
region as in EGFR insertion mutations and occur in
the same subpopulation as those with EGFR muta-
tions (adenocarcinoma, never smoker, East Asian,
and woman) [68,91,92]. So far no small molecule
inhibitors show similar potency against HER2muta-
tions as seenwith EGFR TKIs and studies are needed
to see if mutant HER2 lung cancers respond to the
anti-HER2 antibody trastuzumab. HER4 mutations
were found in (2.3%) NSCLC tumor samples from
Asian patients including male smokers [93].
EGFR mutations occur as preneoplastic lesions
occurring in histologically normal bronchial epithe-lial cells adjacent to tumors with EGFR mutations.
The discovery of EGFR mutations could be used
as an early detection marker and chemoprevention
target [94]. Transgenic mice with either EGFR point
mutations or deletion mutations develop lung ade-
nocarcinomas with similar histology to those seen
in patients [95,96]. When the mutant gene was
“turned-off” in the mice through controlled gene
expression the lung tumors all regressed indicating
thatmutant EGFR is required for both initiation and
maintenance of the tumors.
c-KIT
SCLC but not NSCLC frequently express (40–70%)
both the receptor c-KIT and its ligand, stem cell fac-
tor (SCF) suggesting an autocrine loopmay promote
the growth of the SCLC cells [97]. However, unlike
gastrointestinal stromal tumors which frequently
contain c-KITmutations, activating c-KITmutations
are very rare in lung cancer [98,99].While imatinib,
an inhibitor of c-KIT kinase, inhibits cell growth in
some c-KIT expressing SCLC cell lines in vitro, two
phase II clinical studies and amouse xenograft study
failed to showtumor regression in SCLC by imatinib
monotherapy [100–103].