• What is EGFR?
  • EGFR in Lung Cancer
  • EGFR c.2303G>T (S768I)
  • 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.2303G>T (S768I) Mutation in Lung Cancer

Properties
Location of mutation Kinase domain (exon 20)
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 S768I mutations in EGFR-mutated NSCLC 1.5–3% of untreated EGFR-mutated tumors (Costa et al. 2016)
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. 2006).

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. 2006; Hellmann 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. 2016).

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 S768I (FDA 2018).

Contributors: Christine M. Lovly, M.D., Ph.D.

Suggested Citation: Lovly, C. 2018. EGFR c.2303G>T (S768I) Mutation in Lung Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/egfr/348/ (Updated January 18).

Last Updated: January 18, 2018

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