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each paragraph contain 300 words at least
include 8-10 reference with Citing those in essay (be sure all references are in text writing cited )
Include Tables and Figures from Literature ( needed  3-4) with title  below
plagiarism must be 0%
here the  the topic of paragraph  u must be write about it and each one separate from others :

1-About EGFR and signaling with scheme of EGFR Signaling 
2-Write the EGFR mutation testing methods (Capillary or NGS)
3-Few company names ex., LabCorp, MAYO clinic etc.,
4-Show a scheme or histogram about mutations in Lung cancer
5-Write about mutation appears after the inhibitor therapy that is resistance mutations
6-Write about mutation present in EGFR codon 18-21 that kill cancer with inhibitor therapy that is sensitization mutations
the file i upload use it  for answers all this and short your time 🙂

Reading Materials

Román, M. et al. (2018) ‘KRAS oncogene in non-small cell lung cancer: Clinical perspectives on the treatment of an old target’, Molecular Cancer. Molecular Cancer, 17(1), pp. 1–14. doi: 10.1186/s12943-018-0789-x.

DONG, Y., REN, W., QI, J., JIN, B., LI, Y., TAO, H., XU, R., LI, Y., ZHANG, Q. & HAN, B. 2016. EGFR, ALK, RET, KRAS and BRAF alterations in never-smokers with non-small cell lung cancer. Oncology letters, 11, 2371-2378.

THOMPSON, J. C., YEE, S. S., TROXEL, A. B., SAVITCH, S. L., FAN, R., BALLI, D., LIEBERMAN, D. B., MORRISSETTE, J. D., EVANS, T. L. & BAUML, J. 2016. Detection of therapeutically targetable driver and resistance mutations in lung cancer patients by next-generation sequencing of cell-free circulating tumor DNA. Clinical Cancer Research, 22, 5772-5782.

Yokota, T. (2012) ‘Are KRAS/BRAF Mutations Potent Prognostic and/or Predictive Biomarkers in Colorectal Cancers?’, Anti-Cancer Agents in Medicinal Chemistry, 12(2), pp. 163–171. doi: 10.2174/187152012799014968.

Ellison, G. et al. (2013) ‘EGFR mutation testing in lung cancer: A review of available methods and their use for analysis of tumour tissue and cytology samples’, Journal of Clinical Pathology, 66(2), pp. 79–89. doi: 10.1136/jclinpath-2012-201194.

Mutations in the EGFR Pathway | AACC.org. https://www.aacc.org/publications/cln/articles/2013/october/egfr-mutations. Accessed March 14, 2020.

EGFR and KRAS mutations as criteria for treatment with tyrosine kinase inhibitors: retro- and prospective observations in non-small-cell lung cancer – Annals of Oncology. https://www.annalsofoncology.org/article/S0923-7534(19)37561-1/fulltext. Accessed March 14, 2020.

KRAS oncogene in non-small cell lung cancer: clinical perspectives on the treatment of an old target | SpringerLink. https://link.springer.com/article/10.1186/s12943-018-0789-x. Accessed March 14, 2020.

Lung Cancer With an EGFR Mutation: Diagnosis and Treatment. https://www.verywellhealth.com/lung-cancer-with-an-egfr-mutation-4097338. Accessed March 14, 2020.

Anti-EGFR Therapies: Clinical Experience in Colorectal, Lung, and Head and Neck Cancers | Cancer Network. https://www.cancernetwork.com/oncology-journal/anti-egfr-therapies-clinical-experience-colorectal-lung-and-head-and-neck-cancers. Accessed March 14, 2020.

Brambilla, E., and Gazdar, A. (2009). Pathogenesis of lung cancer signalling pathways: roadmap for therapies. Eur Respir J 33, 1485-1497.

Colombino, M., Paliogiannis, P., Cossu, A., Santeufemia, D.A., Sardinian Lung Cancer Study, G., Sini, M.C., Casula, M., Palomba, G., Manca, A., Pisano, M., et al. (2019). EGFR, KRAS, BRAF, ALK, and cMET genetic alterations in 1440 Sardinian patients with lung adenocarcinoma. BMC Pulm Med 19, 209.

Jorge, S.E., Kobayashi, S.S., and Costa, D.B. (2014). Epidermal growth factor receptor (EGFR) mutations in lung cancer: preclinical and clinical data. Braz J Med Biol Res 47, 929-939.

Stewart, E.L., Tan, S.Z., Liu, G., and Tsao, M.S. (2015). Known and putative mechanisms of resistance to EGFR targeted therapies in NSCLC patients with EGFR mutations-a review. Transl Lung Cancer Res 4, 67-81.

SU, S. & WU, Y.-L. 2017. Clinical trials of tyrosine kinase inhibitors for lung cancer in China: a review. Journal of hematology & oncology, 10, 147.

SESHACHARYULU, P., PONNUSAMY, M. P., HARIDAS, D., JAIN, M., GANTI, A. K. & BATRA, S. K. 2012. Targeting the EGFR signaling pathway in cancer therapy. Expert opinion on therapeutic targets, 16, 15-31.

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Nan, X., Xie, C., Yu, X., and Liu, J. (2017). EGFR TKI as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer. Oncotarget 8, 75712.

Citri, A., and Yarden, Y. (2006). EGF–ERBB signalling: towards the systems level. Nature reviews Molecular cell biology 7, 505-516.

Herbst, R.S. (2004). Review of epidermal growth factor receptor biology. International Journal of Radiation Oncology Biology and Physics 59, S21-S26.

Sharma, S.V., Bell, D.W., Settleman, J., and Haber, D.A. (2007). Epidermal growth factor receptor mutations in lung cancer. Nature Reviews Cancer 7, 169-181.

Mazza, V., and Cappuzzo, F. (2017). Treating EGFR mutation resistance in non-small cell lung cancer–role of osimertinib. The application of clinical genetics 10, 49.

AF Gazdar. Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene. 2009 August ; 28(Suppl 1): S24–S31.doi:10.1038/onc.2009.198

AlyssaM.Krasinskas. EGFR Signaling in Colorectal Carcinoma. Pathology Research International Volume 2011, Article ID 932932, 6 pages doi:10.4061/2011/932932

Morgillo F, Della Corte CM, Fasano M, et al. Mechanisms of resistance to EGFR-targeted drugs: lung cancer. ESMO Open 2016;1: e000060. doi:10.1136/ esmoopen-2016-000060

Zhenfang Du and Christine M. Lovly. Mechanisms of receptor tyrosine kinase activation in cancer. Molecular Cancer (2018) 17:58 https://doi.org/10.1186/s12943-018-0782-4

Marta Román, Iosune Baraibar, Inés López, Ernest Nadal, Christian Rolfo, Silvestre Vicent and Ignacio Gil-Bazo. KRAS oncogene in non-small cell lung cancer: clinical perspectives on the treatment of an old target. Molecular Cancer (2018) 17:33 https://doi.org/10.1186/s12943-018-0789-x

Ammad Ahmad Farooqia, Marc de la Rocheb, Mustafa B.A. Djamgozc,d, Zahid H. Siddike. Overview of the oncogenic signaling pathways in colorectal cancer: Mechanistic insights. Seminars in Cancer Biology, Volume 58, October 2019, Pages 65-79. https://doi.org/10.1016/j.semcancer.2019.01.001

Lung cancer is the leading cause of cancer death,
accounting for one third of all deaths from cancer
worldwide. Like most cancers, lung cancer is a con-
glomeration of diseases of diverse aetiology, broadly
divided into small-cell lung cancer (SCLC, comprising
20% of lung cancers), and non-small-cell lung cancer
(NSCLC, comprising 80% of lung cancers). SCLC is a
tumour of neural crest origin and initially responds well
to chemotherapy, but commonly recurs with resistant
disease. NSCLC is thought to originate in lung epithe-
lial cells, and comprises diverse histological subtypes
including adenocarcinoma, bronchioloalveolar, squa-
mous, anaplastic and large-cell carcinomas1. Most
patients with advanced NSCLC present with metastatic
disease and, if left untreated, have a median survival
after diagnosis of 4–5 months and a 1-year survival of
less than 10% (REF. 2). Combination cytotoxic chemo-
therapy, the treatment of choice in these cases, results
in a modest increase in survival at the cost of signifi-
cant toxicity to the patient3. The advent of molecular-
targeted therapeutics has therefore generated much
optimism, given the perception that the limits of
chemotherapy in NSCLC have been reached and that
further advances in the treatment of NSCLC will have
to involve radically different approaches (reviewed in
REF. 4). Against this backdrop, the approval of small-
molecule inhibitors of the epidermal growth factor
receptor (EGFR) kinase for the treatment of NSCLC
in 2003 was heralded with much fanfare, although
the limitations of their efficacy have become readily
apparent (reviewed in REF. 5).

The deregulation of EGFR in NSCLC
The receptor tyrosine kinase (RTK) super-family of cell-
surface receptors serve as mediators of cell signalling
by extra-cellular growth factors6. Members of the ErbB
family of RTKs, such as EGFR (also known as ERBB1
or HER1), ERBB2 (also known as HER2), ERBB3 (also
known as HER3) and ERBB4 (also known as HER4)
have received much attention, given their strong asso-
ciation with malignant proliferation (reviewed in REF. 7).
Increased levels of EGFR gene expression are observed
in cancers of the head and neck, ovary, cervix, bladder,
oesophagus, stomach, brain, breast, endometrium,
colon and lung, and frequently seem to confer an
adverse prognosis (reviewed in REFS 6,8). Extending
previous observations of almost two decades ago9,10,
recent retrospective analyses have reported EGFR over-
expression in 62% of NSCLC cases, and its expression
is correlated with a poor prognosis8,11,12. In some cases,
genomic analyses documented the amplification of
chromosomal region 7p12, where the EGFR gene is
located13. In addition to EGFR overexpression, its
cognate ligands, epidermal growth factor (EGF) and
transforming growth factor-α (TGFα) are also fre-
quently expressed in NSCLCs, and can establish autocrine
loops that lead to receptor hyperactivity14,15. The disrup-
tion of these autocrine loops is the primary rationale for
antibody-based EGFR-targeted therapeutics16.

Various strategies involving small-molecule inhibi-
tors have also been developed to target EGFR and/or
its family members, and these are in various stages
of clinical testing (reviewed in REF. 17). Gefitinib

*Massachusetts General
Hospital Cancer Center and
Harvard Medical School, 149
13th Street, Charlestown,
Massachusetts 02129, USA.
‡Present address: National
Human Genome Research
Institute, National Institutes
of Health, Bethesda,
Maryland 20892, USA.
Correspondence to D.A.H.
e-mail: [email protected]
harvard.edu
doi:10.1038/nrc2088

Neural crest
A pluripotent, ectodermally
derived ridge-like cluster of
cells found on either side of the
neural tube in vertebrate
embryos.

Cytotoxic chemotherapy
Chemicals or drugs that kill
proliferating cells, especially
cancer cells. Their side effects
are typically related to the
inhibition of normal cell
proliferation, with a narrow
window of selectivity for
cancer cells.

Epidermal growth factor receptor
mutations in lung cancer
Sreenath V. Sharma*, Daphne W. Bell*‡, Jeffrey Settleman* and Daniel A. Haber*

Abstract | The development and clinical application of inhibitors that target the epidermal
growth factor receptor (EGFR) provide important insights for new lung cancer therapies, as
well as for the broader field of targeted cancer therapies. We review the results of genetic,
biochemical and clinical studies focused on somatic mutations of EGFR that are associated
with the phenomenon of oncogene addiction, describing ‘oncogenic shock’ as a
mechanistic explanation for the apoptosis that follows the acute treatment of susceptible
cells with kinase inhibitors. Understanding the genetic heterogeneity of epithelial tumours
and devising strategies to circumvent their rapid acquisition of resistance to targeted
kinase inhibitors are essential to the successful use of targeted therapies in common
epithelial cancers.

NATURE REVIEWS | C A N C E R VO LU M E 7 | M A R C H 2 0 0 7 | 169

REVIEWS

© 2007 Nature Publishing Group

Molecular-targeted
therapeutics
Chemicals or drugs that target
known proteins that are
important in cancer cell
proliferation or survival at the
same time as being
dispensable to normal cells.
Although side effects are
typically less severe than with
cytotoxic agents, the effective
inhibition of the target protein
might not translate into
generally effective therapies,
hence the importance of
reliable biomarkers.

Autocrine loop
A mode of cell signalling in
which soluble ligands released
by cells stimulate receptors on
their own cell surfaces.

Reversible inhibitors
Inhibitors that bind non-
covalently with biological
molecules and interfere with
their activity.

(Iressa; AstraZeneca) and erlotinib (Tarceva; OSI
Pharmaceuticals, Genentech), two small-molecule drugs
that specifically target the tyrosine kinase activity of
EGFR (EGFR-tyrosine kinase inhibitors (EGFR-TKIs)),
received fast-track approval from the US Food and Drug
Administration (FDA) in 2003 and 2004, respectively,
for patients with advanced NSCLC who had failed to
respond to conventional chemotherapy5. Both drugs are
reversible inhibitors of the EGFR kinase, designed to act as
competitive inhibitors of ATP-binding at the active site
of the EGFR kinase18,19. The observation that sensitivity
to gefitinib and erlotinib correlated very strongly with a
newly discovered class of somatic activating mutations
in the EGFR kinase domain20–22 explained the unique
subset of drug-responsive cases, notably those aris-
ing in non-smokers and more frequently in women,
individuals of Asian ethnic background and those with
adenocarcinoma and bronchioloalveolar histology (for
a review of the recent clinical literature see Sequist
et al.23). In addition to providing a genetic marker for
a highly EGFR-TKI-responsive subset of NSCLCs, this
correlation has also highlighted the crucial importance
of mutationally activated kinases as anticancer drug
targets (reviewed in REF. 24) (FIG. 1).

In unselected NSCLC samples, EGFR mutations are
present in ~10% of cases in North America and Western
Europe, but ~30–50% of cases in individuals of East Asian
descent, and are associated with most (over 50%) adeno-

carcinomas with bronchioloalveolar features that arise in
non-smokers25–34. EGFR kinase domain mutations target
four exons (18–21), which encode part of the tyrosine
kinase domain (the entire kinase domain is encoded by
exons 18–24) and are clustered around the ATP-binding
pocket of the enzyme25,35–39. Consistent with their pur-
ported role in the aetiology of NSCLC, recent studies
have shown that exon 19 deletions that involve the LREA
motif, L858R, G719S and ins 770(NPG)-mutated EGFR
proteins are oncogenic in both cell culture and transgenic
mouse studies40–42. These mutations also increase the
kinase activity of EGFR, leading to the hyperactivation
of downstream pro-survival pathways, and consequently
confer oncogenic properties on EGFR43–45.

Kinase domain mutations in EGFR are generally
referred to as activating mutations, as they seem to result
in the increased kinase activity of the receptor. However,
this does not imply that these mutated EGFRs are
necessarily constitutively or fully active, as their degree of
ligand independence might be a function of experimental
context40,43,44,46,47. These partially activated mutant EGFRs
can be rendered fully ligand-independent, and therefore
constitutively active, by second site substitutions in EGFR,
such as the T790M mutation in exon 20 (REF. 46). In vitro
biochemical studies using purified recombinant wild-type
and mutant (L858R and ∆E746–A750) EGFR cytoplasmic
domains have shown that mutants have increased kcat
values and an increased Km for ATP48,49. Moreover, as has
been observed in cell-based studies, the mutants show an
increased sensitivity to inhibition by erlotinib (reduced Ki)
in these in vitro kinase assays. The reduced ATP affinity
seen with mutant kinases most probably accounts for their
increased sensitivity to the selective EGFR-TKIs, which
compete with ATP for binding to the catalytic site. Another
study, in which the phage-display method was used to exam-
ine the interaction of a large panel of kinases with selective
inhibitors, concluded that EGFR mutations, includ-
ing ∆E746-A750, do not themselves affect the affinity
for gefitinib and erlotinib50.

EGFR-targeted therapy of NSCLC
For unknown reasons, EGFR kinase domain mutations
seem to be restricted to a subset of NSCLC, although
very rare mutations have also been reported in SCLC,
cholangiocarcinoma, ovarian, colorectal, head and neck,
oesophageal and pancreatic cancers51–56. This Review
discusses the genetic and biochemical determinants of
erlotinib and gefitinib sensitivity in NSCLC. In light
of the rapid acquisition of resistance to these EGFR-TKIs,
we discuss the mechanisms by which resistance might
occur and the possibilities for alternative therapeutics.

Genetic determinants of sensitivity to gefitinib and erlo-
tinib. Early NSCLC clinical trials with gefitinib and erlo-
tinib were modestly encouraging, with partial responses
observed in approximately 10% of treated patients with
NSCLC57–60. Most responses were seen in East Asians,
females or non-smoking patients with NSCLC. These
patients had a high frequency of adenocarcinoma
with bronchioloalveolar features, and many showed a
dramatic and lasting response to second- or third-line

At a glance

• Advanced non-small-cell lung cancer (NSCLC) is the leading cause of cancer-
related deaths in the world.

• Epidermal growth factor receptor (EGFR) is expressed in 50% of NSCLCs, and its
expression is correlated with poor prognosis. These two factors make EGFR and its
family members prime candidates for the development of targeted therapeutics.

• Two EGFR-targeting small-molecule inhibitors, gefitinib (Iressa: AstraZeneca,
approved in May 2003) and erlotinib (Tarceva: OSI-Genentech, approved in
November 2004) received fast-track approval from the US Food and Drug
Administration as treatment for patients with advanced NSCLC who had failed to
respond to conventional chemotherapy.

• Early clinical data showed that 10% of patients with NSCLC responded to
gefitinib or erlotinib. Although infrequent, the speed and magnitude of clinical
responses were unique, as was the fact that they were seen in specific subsets of
cases (non-smokers, women, East Asians and patients with adenocarcinomas with
bronchioloalveolar histology).

• Molecular analysis showed that in most instances, responders harboured specific
mutations in the gene that encodes EGFR. Exon 19 mutations characterized by
in-frame deletions of amino-acids 747–750 account for 45% of mutations, exon 21
mutations resulting in L858R substitutions account for 40–45% of mutations, and
the remaining 10% of mutations involve exon 18 and 20.

• EGFR kinase domain mutations hyperactivate the kinase and confer a dependence
on the mutated kinase for the survival of the NSCLC tumour cells.

• The treatment of sensitive cells with targeted therapeutics such as gefitinib and
erlotinib seems to trigger a form of ‘oncogenic shock’, which is postulated to result
from the differential decay of downstream signals leading to a temporary
predominance of apoptotic signals.

• Acquired resistance to gefitinib and erlotinib might involve the recurrent mutation
T790M which affects the gatekeeper residue in the catalytic domain of the kinase
that weakens the interaction of the inhibitor with its target. Resistance can be
overcome in vitro by irreversible inhibitors of EGFR

R E V I E W S

170 | M A R C H 2 0 0 7 | VO LU M E 7 w w w.nature.com/reviews/cancer
© 2007 Nature Publishing Group

∆E746-A750
∆E746-T751
∆E746-A750 (ins RP)
∆E746-T751 (ins A/I)
∆E746-T751 (ins VA)
∆E746-S752 (ins A/V)
∆L747-E749 (A750P)
∆L747-A750 (ins P)
∆L747-T751
∆L747-T751 (ins P/S)
∆L747-S752
∆L747-752 (E746V)
∆L747-752 (P753S)
∆L747-S752 (ins Q)
∆L747-P753
∆L747-P753 (ins S)
∆S752-I759

L858R (40–45%)
N826S
A839T
K846R
L861Q
G863D

V765A
T783A

G719C
G719S
G719A
V689M
N700D
E709K/Q
S720P

68
8

72
8

72
9

76
1

76
2

82
3

82
4

87
5

Autophosphorylation

Exon 2 5 1613 17 18–21 28

EGF binding EGF binding Tyrosine kinase

7 22–24

Exon 18
(nucleotide-binding loop)

Exon 19 Exon 21
(activation loop)

Exon 20

D761Y

T790M (50%)*
D770_N771 (ins NPG)
D770_N771 (ins SVQ)
D770_N771 (ins G), N771T
V769L
S768I

TM

(5%)

(45%)

(<1%)

(40–45%)

(5%)(3 years), but in most cases they only
last for ~6–12 months before resistant disease recurs.
Given the low frequency of EGFR-mutant NSCLC, a
modest (2–3 months) improvement in overall survival
has been observed in US and European retrospective
trials, driven primarily by the stabilization of disease
rather than tumour shrinkage, which is not tightly
linked to the presence of EGFR mutations31. In these
studies, increased EGFR gene copy number and high
levels of aneuploidy, as measured by FISH, seemed to be
more predictive of disease stabilization after treatment
with TKIs59,82. The effect on overall survival in genotypi-
cally uncharacterized cases was observed with erlotinib
(BR21 trial), but not gefitinib (ISEL trial), contributing
to the withdrawal of gefitinib from the US and European
market and the approval of erlotinib as third-line therapy
in NSCLC irrespective of tumour genotype59,82. A closer
examination reveals differences in the dose of the two
agents, together with differences in the composition
of the patient population that might account for the
observed differences in outcome between gefitinib and
erlotinib83 (FIG. 2). Nonetheless, gefitinib (which is still
in use in Asia) and erlotinib are comparable in virtually
all laboratory analyses, and the appropriate clinical role
of EGFR mutation analysis in the treatment of NSCLC
remains an evolving question, awaiting prospective
studies with adequate tumour analysis.

Biochemical determinants of sensitivity to gefitinib
and erlotinib. Unpublished results from our laboratory
suggest that sensitivity to EGFR-TKIs is not simply
recapitulated by expressing the mutant constructs in
transfected cells, pointing to the importance of cell-
ular context in conferring dependency on the EGFR
pathway. Furthermore, caution should be exercised
in interpreting in vitro data using NSCLC cell lines
as surrogates for clinical responses (FIG. 3). However,
in vitro studies with NSCLC cell lines have highlighted
the fact that gefitinib- and erlotinib-sensitizing muta-
tions invariably hyperactivate the EGFR signalling
pathway and promote EGFR-mediated anti-apoptotic
and pro-survival signals through the Ras–Raf–MEK
(mitogen-activated and extracellular-signal regulated
kinase kinase)–ERK1 and ERK2 (extracellular-signal-
regulated kinase 1 and 2), PI3K–Akt (phosphatidyli-
nositol-3 kinase–Akt) and STAT3 and STAT5 (signal

Figure 2 | Why gefitinib failed in the United States. a | The maximum tolerated dose
(MTD) for gefitinib and erlotinib, and the dose of the two drugs used in the ISEL and
BR21 trials. Although erlotinib was used at its MTD in the BR21 trial, gefitinib was used
at the sub-MTD level of 250 mg a day. b | The composition of the patients and their
response to chemotherapy at the time of recruitment for the ISEL and BR21 trials. The
histogram represents patients with progressive disease (orange), stable disease (green)
and partial response (yellow). Note that the patient pool recruited to the ISEL trial had
a significantly larger percentage of individuals with progressive disease as compared
to patients recruited to the BR21 trial (45% versus 28%), and conversely had a lower
percentage of patients that had a partial response to chemotherapy (18% versus 38%).
Also shown are the inclusion criteria for patient enrollment in both of the trials. In the
ISEL trial, only patients who had progressive disease within 90 days of cessation of
chemotherapy were included, but no similar time-limited exclusion criterion was
implemented for the inclusion of patients in the BR21 trial83. The differences in dosage
used and the patient selection criteria might have contributed to the differences in
outcomes between the two trials.

R E V I E W S

172 | M A R C H 2 0 0 7 | VO LU M E 7 w w w.nature.com/reviews/cancer
© 2007 Nature Publishing Group

Hypersensitive SensitiveSensitivity

Clinical dose of gefitinib (G) or erlotinib (E)

250 mg day–1 150 mg day–1

Insensitive

In vitro
equivalent
(µM) 0.0001 0.001 0.01 0.1 1 10

NSCLC
cell lines

Genetic
signatures

NCI H2170
(200 nM)

NCI H2073
(250 nM)

NCI-H3255 (1 nM)
PC9 (4 nM)

NCI-H1975
(12 µM)

NCI-H1650
(9 µM)

NCI-H460
(20 µM)

EGFR: wild typeEGFR: L858R
EGFR: ∆(E746-A750)

EGFR: T790M
PTEN loss
KRAS

G E

Oncogenic shock
A mechanism to explain
oncogene addiction, in which
the acute inactivation of an
oncoprotein is associated with
differential attenuation rates of
pro-survival and pro-apoptotic
signals emanating from the
oncoprotein, such that
apoptotic signals become
predominant and kill the
cancer cell.

Differential signal decay
A signalling imbalance created
by the rapid decay of pro-
survival signals and
persistence of the relatively
long-lived pro-apoptotic
signals after acute oncogene
inactivation.

transducer and activator of transcription proteins 3
and 5) pathways such that cancer cells might become
dependent on a functional EGFR for their survival43,84–86.
Interestingly, these are the same pathways that are
activated after ligand engagement and are inhibited
by gefitinib, including the ERK pathway involved in
cell proliferation and the pro-survival Akt pathway87–89.
The obvious implication is that shutting off EGFR
with specific kinase inhibitors, antibodies or RNA
interference would extinguish these proliferative and
survival signals on which the tumour cell is dependent,
therefore resulting in tumour cell death. Normal cells
(or non-EGFR-dependent tumour cells that do not
respond to gefitinib or erlotinib) remain unaffected,
as their pro-survival signals are either driven by other
genes or can be compensated for by other RTKs in
the event of EGFR inhibition. This is consistent with the
observation that gefitinib and erlotinib response in sen-
sitive cells results in the downregulation of ERK, Akt and
STAT3 and STAT5, whereas a similar downregulation
is not evident in insensitive or resistant cells43,87–90.

Although these pro-survival signalling pathways are
probably controlled by many RTK outputs in normal
cells, their dependency on mutated and/or activated
EGFR in some NSCLC tumours and cell lines bears the
hallmark of oncogene addiction (BOX 1).

The molecular mechanisms that underpin onco-
gene addiction remain to be elucidated. As commonly
understood, alterations of the signal-transduction
pathways in cancer cells are thought to underlie drug
hypersensitivity91. Based on modelling studies in vitro,
we have recently proposed that unbalanced pro-apop-
totic and pro-survival signals lead to a phenomenon that
we refer to as oncogenic shock, and might account for the
observed apoptotic outcome following the acute inacti-
vation of a crucial oncogene in an addicted cancer cell92
(FIG. 4). According to this model, an addicting oncogene
gives rise to both pro-apoptotic and pro-survival signal
outputs. While the oncogene is active, the pro-survival
signals pre-dominate and keep the pro-apoptotic signals
in check, enabling the survival and proliferation of
the cancer cell. After acute oncogene inactivation, the
relatively short-lived pro-survival signals decay first,
whereas the longer-lasting pro-apoptotic outputs are
maintained during a crucial window of time. Therefore,
differential signal decay leading to a signal imbalance and
a temporary predominance in pro-apoptotic outputs sets
in motion the apoptotic cascade and commits the cell
irrevocably to apoptosis, even if the signalling imbal-
ance is subsequently redressed. In support of the onco-
genic shock model, the apoptotic response to oncogene
inactivation in oncogene-addicted cells is abrogated if
the disruption of oncogene-derived signals is extended
over a period of time, rather than being acute, or if pro-
survival signals are transiently applied during the crucial
window of time following acute withdrawal92. Therefore,
the cell is not hard-wired to …

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