Epidermal growth factor receptor (EGFR)
belongs to a family of receptor tyrosine
kinases (RTKs) that include EGFR/ERBB1,
HER2/ERBB2/NEU, HER3/ERBB3, and HER4/ERBB4. The binding of ligands, such as epidermal growth
factor (EGF), induces a conformational change that facilitates receptor homo- or heterodimer formation, thereby
resulting in activation of EGFR tyrosine kinase
activity. Activated EGFR then phosphorylates its substrates, resulting in activation of
multiple downstream pathways within the cell, including the PI3K-AKT-mTOR pathway, which is
involved in cell survival, and the RAS-RAF-MEK-ERK pathway, which is involved in cell
proliferation (Figure 1).
Figure 1. Schematic of EGFR signaling pathway. Growth factor binding to
EGFR results in activation of the MAPK signaling pathway
(RAS-RAF-MEK-ERK) and the PI3K pathway (PI3K-AKT-mTOR). The letter "K" within the schema
denotes the tyrosine kinase domain.
Suggested Citation: Lovly, C., L. Horn, W. Pao. 2015. EGFR. My Cancer
(Updated December 7).
Last Updated: December 7, 2015
EGFR in Non-Small Cell Lung Cancer (NSCLC)
Approximately 10% of patients with NSCLC in the US and 35% in East Asia have tumor associated
EGFR mutations (Lynch et al. 2004;
al. 2004; Pao et al. 2004). These mutations occur
within EGFR exons 18–21, which encodes a portion of the EGFR kinase domain (Figure 1). EGFR
mutations are usually heterozygous, with the mutant allele also showing gene amplification (Soh et al. 2009).
Approximately 90% of these mutations are exon 19 deletions or exon 21 L858R point mutations
(Ladanyi and Pao 2008).
These mutations increase the kinase activity of EGFR, leading to hyperactivation of
downstream pro-survival signaling pathways (Sordella et al. 2004).
Regardless of ethnicity, EGFR mutations
are more often found in tumors from female never smokers (defined as less than 100
cigarettes in a patient's lifetime) with adenocarcinoma histology (Lynch et al. 2004;
al. 2004; Pao et al. 2004). However, EGFR
mutations can also be found in other subsets of NSCLC, including in former and current
smokers as well as in other histologies.
In the vast majority of cases, EGFR mutations
are non-overlapping with other oncogenic mutations
found in NSCLC (e.g., KRAS mutations, ALK rearrangements, etc.).
Figure 1. Schematic of EGFR mutations. Exons 18–21 of the EGFR
kinase domain are depicted. Mutations above the schematic are
associated with sensitivity to EGFR TKIs. Mutations
listed below the schematic are associated with EGFR TKI resistance.
a While most exon 20 insertions are associated with decreased EGFR TKI
sensitivity, the EGFR A763_Y764insFQEA mutation is an exception and has been associated in
retrospective studies with increased EGFR TKI sensitivity (Yasuda et al.
Suggested Citation: Lovly, C., L. Horn, W. Pao. 2015. EGFR in Non-Small Cell
Lung Cancer (NSCLC). My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/egfr/
(Updated June 18).
Last Updated: June 18, 2015
EGFR c.2303G>T (S768I) Mutation in Lung Cancer
|Location of mutation
Kinase domain (exon 20)
|Frequency of EGFR mutations
||~10% in the USA
~35% in Asia
(Lynch et al. 2004;
Paez et al. 2004;
Pao et al. 2004)
|Frequency of EGFR S768I mutations
in EGFR-mutated NSCLC
||1.5–3% of untreated EGFR-mutated tumors (Costa et al.
|Implications for Targeted Therapeutics
|Response to first generation EGFR TKIs (erlotinib, gefitinib)
||Unknown at this timea
|Response to second generation EGFR TKIs (afatinib, dacomitinib, neratinib)
||Confers increased sensitivityb
|Response to third generation (mutant specific) EGFR TKIs
||Unknown at this time
|Response to anti-EGFR antibodies
||Currently no role for EGFR mutation
in predicting response in NSCLC
The S768I mutations results in an amino acid substitution at position 768 in
EGFR, from a serine (S) to an isoleucine (I). This mutation
occurs within exon 20, which encodes part of the kinase
domain. Preclinical data suggest cells expressing EGFR S768I have sustained tyrosine phosphorylation in response to EGF
stimulation and reduced ubiquitination in comparison to wild-type receptor (Chen et al.
a Preclinical and case report evidence for response to first-generation
EGFR TKIs in patients with EGFR S768I and patients with compound EGFR mutations including EGFR S768I are mixed, with some
clinical cases reporting good response and others reporting rapid progression on
first-generation EGFR TKI therapy (Asahina et al. 2006; Chen et al.
et al. 2014; Kobayashi
et al. 2013; Leventakos
et al. 2016; Masago
et al. 2010; Pallan
et al. 2014; Svaton
et al. 2015; Weber
et al. 2014; Wu
et al. 2008). Computational studies suggest sensitivity to both erlotinib and
gefitinib for single S768I mutations (Raghav et al. 2013). More
recent clinical studies in Taiwan and China found that patients harboring EGFR S768I were
sensitive to EGFR TKI therapy with gefitinib and erlotinib, though less so than patients
with more common EGFR activating mutations such as EGFR L858R (Chen et al.
2016; Chiu et
al. 2015). Meta-analysis results across multiple trials of patients harboring EGFR
S768I agree that this mutation confers a good outcome with erlotinib, although they were
unable to confirm sensitivity or resistance (Klughammer et al.
b Preclinical and clinical trial data suggest that EGFR S768I is
sensitive to afatinib, with all 8 enrolled patients, which included 1 patient with a single
S768I mutation and 7 patients with
compound mutations, experiencing an
objective response (Banno
et al. 2016; Yang
et al. 2015). Among these 8 patients, the median progression-free survival was 14.7
months (Yang et al.
2015). The indication for afatinib has been expanded to include patients with NSCLC
in the metastatic setting whose tumors harbor rare EGFR mutations such as G719X, L861Q, and
Suggested Citation: Lovly, C. 2018. EGFR c.2303G>T (S768I) Mutation in Lung Cancer. My Cancer
(Updated January 18).
Last Updated: January 18, 2018
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