• What is EGFR?
  • EGFR in Lung Cancer
  • EGFR Exon 20 Insertion
  • 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 Exon 20 Insertion in Non-Small Cell 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 exon 20 insertion mutations in EGFR-mutated NSCLC 4–9.2% (Arcila et al. 2013; Mitsudomi and Yatabe 2010; Oxnard et al. 2013)
Implications for Targeted Therapeutics
Response to EGFR TKIs Confers decreased sensitivitya
Response to anti-EGFR antibodies Currently no role for EGFR mutation in predicting response in NSCLC
Response to HSP-90 inhibitors Unknown at this timeb

EGFR exon 20 insertions comprise approximately 4–9.2% of all EGFR-mutated lung tumors (Arcila et al. 2013; Mitsudomi 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; Li et al. 2008; Yasuda, Kobayashi, and Costa 2012Yasuda 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. 2013).

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; Wu et 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.

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Contributors: Daniel B. Costa, M.D., Ph.D., M.MSc.

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

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