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 Exon 20 Insertion in Non-Small Cell Lung Cancer
EGFR exon 20 insertions comprise approximately 4–9.2% of all EGFR-mutated lung
tumors (Arcila et al.
and Yatabe 2010; Oxnard et al. 2013). Most EGFR exon 20
insertions occur in between amino acids
767 to 774 of exon 20, within the loop that follows the C-helix of the kinase domain of EGFR (Yasuda,
Kobayashi, and Costa 2012).
a EGFR exon 20 insertion mutants, outside of A763_Y764insFQEA, are
associated in preclinical models, for the most part, with lower sensitivity to clinically achievable
doses of the reversible EGFR TKIs, erlotinib (Tarceva) and gefitinib (Iressa), and of the
irreversible EGFR TKIs neratinib, afatinib (Gilotrif), and dacomitinib (Engelman et al. 2007;
al. 2008; Yasuda, Kobayashi, and
Costa 2012; Yasuda et al. 2013; Yuza et al. 2007),
and of the mutant-selective covalent EGFR TKIs WZ4002 (Zhou et al. 2009)
and CO-1686 (Walter et
al. 2013). The crystal structure of a representative TKI-insensitive mutant
(D770_N771insNPG) reveals it has an unaltered ATP-binding pocket and that, unlike
EGFR sensitizing mutations, it
activates EGFR without increasing its affinity for EGFR TKIs (Yasuda et al.
Patients with tumors harboring EGFR exon 20 insertion mutations
involving amino acids A767, S768, D770,
P772 and H773 display lack of response when treated with gefitinib or erlotinib (Wu et al. 2008;
al. 2011; Yasuda, Kobayashi, and Costa 2012).
In retrospective and prospective analyses of patients with NSCLCs harboring typical EGFR
exon 20 insertions, most displayed progressive disease in the course of treatment with
gefitinib or erlotinib or afatinib (Yasuda, Kobayashi, and Costa 2012;
Yasuda et al. 2013).
b In preliminary results from a phase II trial of non-small cell lung
cancer patients with tumors harboring EGFR exon 20 insertions treated with the HSP-90
inhibitor AUY922, one patient experienced a partial response and two patients experienced
stable disease in the initial 10-patient cohort, with a median progression free-survival of
6.1 months (Piotrowska
et al. 2015).
For information about a specific exon 20 insertion, please fill out the DIRECT request form. DIRECT catalogues drug response data from
patients with non-small cell lung cancer whose tumors harbor mutations in EGFR.
Suggested Citation: Costa, D. 2015. EGFR Exon 20 Insertion in Non-Small Cell
Lung Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/egfr/64/
(Updated November 5).
Last Updated: November 5, 2015
My Cancer Genome has released its new and improved cancer clinical trials search tool on our
beta website. Please visit beta.padiracinnovation.org
to check it out!