• What is EGFR?
  • EGFR in Lung Cancer
  • EGFR c.2155G>T (G719C)
  • Clinical Trials

EGFR

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).

mapk-pk13.png

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.

Related Pathways

Contributors: Christine M. Lovly, M.D., Ph.D., Leora Horn, M.D., M.Sc., William Pao, M.D., Ph.D. (through April 2014)

Suggested Citation: Lovly, C., L. Horn, W. Pao. 2015. EGFR. My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/egfr/?tab=0 (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; Paez et 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; Paez et 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.).

egfr-nsclc.png

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. 
NOTE: 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. 2013).

 

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Contributors: Christine M. Lovly, M.D., Ph.D., Leora Horn, M.D., M.Sc., William Pao, M.D., Ph.D. (through April 2014)

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.2155G>T (G719C) Mutations in Non-Small Cell Lung Cancer

Properties
Location of mutation Kinase domain (exon 18)
Frequency of EGFR mutations in NSCLC ~10% in the USA
~35% in Asia
(Lynch et al. 2004; Paez et al. 2004; Pao et al. 2004)
Frequency of EGFR G719C mutations in EGFR-mutated NSCLC 0.3% (COSMIC 2015​)
Implications for Targeted Therapeutics
Response to EGFR TKIs Confers increased sensitivitya
Response to second-generation EGFR TKIs (afatinib) Confers increased sensitivityb
Response to anti-EGFR antibodies Currently no role for EGFR mutation in predicting response in NSCLC

The G719C mutation results in an amino acid substitution at position 719 in EGFR, from a glycine (G) to a cysteine (C). This mutation occurs within exon 18, which encodes part of the kinase domain. Several additional independent mutations have also been described at position 719: G719A, G719D, G719S, and G719V. Collectively, these point mutations occur with a frequency of approximately 2-3% in EGFR-mutated lung tumors (COSMIC 2015​; Mitsudomi and Yatabe 2010).

a This mutation is associated with increased sensitivity to the EGFR TKIs, erlotinib (Tarceva) and gefitinib (Iressa; Han et al. 2005; Lynch et al. 2004; Rosell et al. 2005; Taron et al. 2005). Of note, in a trial of the irreversible pan-ErbB TKI, neratinib (HKI-272), 3 of 4 patients with EGFR G719X mutation had a partial response (Sequist et al. 2010).

b 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 S768I (FDA 2018).

 

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Contributors: Christine M. Lovly, M.D., Ph.D., Leora Horn, M.D., M.Sc., William Pao, M.D., Ph.D. (through April 2014)

Suggested Citation: Lovly, C., L. Horn, W. Pao. 2018. EGFR c.2155G>T (G719C) Mutations in Non-Small Cell Lung Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/egfr/2/ (Updated January 18).

Last Updated: January 18, 2018

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