• What is EGFR?
  • EGFR in Lung Cancer
  • EGFR Kinase Domain Duplication
  • 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 18–25 Kinase Domain Duplication (EGFR-KDD) in Non-Small Cell Lung Cancer

Properties
Location of mutation Kinase domain (exons 18–25)
Frequency of canonical 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 18–25 duplication in EGFR-mutated NSCLC Uncertain at this time
Implications for Targeted Therapeutics
Response to EGFR TKIs Confers increased sensitivitya
Response to anti-EGFR antibodies Currently no role for EGFR mutation in predicting response in NSCLC

The EGFR-kinase domain duplication (EGFR-KDD) results from an in-frame tandem duplication of EGFR exons 18–25, which encode the entire EGFR tyrosine kinase domain. In vitro, EGFR-KDD is constitutively active and demonstrates oncogenic properties. In silico modeling suggests that the mechanism by which the EGFR-KDD confers constitutive activity through the formation of intramolecular dimers.

a Both preclinical and case report evidence suggest that EGFR-KDD has increased sensitivity to EGFR-TKIs.

Reference Study Type Diagnosis Alteration Line of Treatment Treatment Best Response Duration of Response
Gallant et al. 2015 Case report Stage IV lung adenocarcinoma EGFR exon 18–25 duplication Second afatinib Partial response 7 cycles of therapy
Baik et al. 2015 Case report Recurrent bronchoalveolar carcinoma, nonmucinous type EGFR exon 18–25 duplication Second gefitinib Partial response 6 years
Fourth erlotinib Partial response 3 years

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

Suggested Citation: Lovly, C. 2015. EGFR exon 18–25 Kinase Domain Duplication (EGFR-KDD) in Non-Small Cell Lung Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/egfr/339/ (Updated December 11).

Last Updated: December 11, 2015

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