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.2390G>C (C797S) Mutation in Lung Cancer
The C797S mutation results in an amino acid substitution at position 797 in
EGFR, from a cysteine (C) to a serine (S). This mutation
occurs within exon 20, which encodes part of the kinase
a Evidence from case reports shows that C797S mutation can be detected in ~40% of EGFR-mutant lung cancers
that have developed acquired resistance to osimertinib (Thress et al. 2015; Wang
et al. 2016). Preclinical studies suggest that in presence of exon 19 deletions or
L858R mutations in combination with T790M, the C797S mutation makes cell-lines resistant to
all EGFR inhibitors (afatinib, gefitinib, WZ4002, CO-1686, and osimertinib) (Ercan et al. 2015; Niderest et al. 2015; Thress et al. 2015). These
studies also showed that in presence of C797S mutation with wild type T790M, cells remained
responsive to first generation inhibitors (Niderest et al. 2015).
Last Updated: October 31, 2017
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