• What is ERBB2?
  • ERBB2 in Lung Cancer
  • Clinical Trials


HER2 belongs to a family of receptor tyrosine kinases (RTKs) that includes EGFR/ERBB1, HER2/ERBB2/NEU, HER3/ERBB3, and HER4/ERBB4. The gene for HER2 is located on chromosome 17 and has been found to be amplified with an increased copy number in several cancers (Jorgensen 2010). Amplification of HER2 has been found to promote tumorigenesis and to be involved in the pathogenesis of several human cancers (Moasser 2007).

To date, no ligand has been identified for HER2. However, HER2 appears to be the preferential dimerization partner for all members of the ERBB family (Graus-Porta et al. 1997). The binding of ligand followed by HER2 hetero-dimerization results in activation of HER2 tyrosine kinase activity. Activated HER2 then phosphorylates its substrates, leading to 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 HER2 signaling pathway. Growth factor binding results HER2 heterodimerization and 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., Chanjuan Shi, M.D., Ph.D., Graham T. Watson, M.D., Leora Horn, M.D., M.Sc., Paula Pohlmann, M.D., Ph.D., Laura W. Goff, M.D.

Suggested Citation: Lovly, C., C. Shi, G. Watson, L. Horn, P. Pohlmann, L. Goff. 2015. HER2 (ERBB2). My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/erbb2/?tab=0 (Updated December 7).

Last Updated: December 7, 2015

HER2 (ERBB2) in Non-Small Cell Lung Cancer (NSCLC)

HER2 mutations are detected in approximately 2–4% of NSCLC (Buttitta et al. 2006; Shigematsu et al. 2005; Stephens et al. 2004). The most common mutation is an in-frame insertion within exon 20. HER2 mutations appear to be found more commonly in never smokers (defined as less than 100 cigarettes in a patient's lifetime) with adenocarcinoma histology (Buttitta et al. 2006; Shigematsu et al. 2005; Stephens et al. 2004). However, HER2 mutations can also be found in other subsets of NSCLC, including in former and current smokers as well as in other histologies (Buttitta et al. 2006; Shigematsu et al. 2005; Stephens et al. 2004). The exon 20 insertion results in increased HER2 kinase activity and enhanced signaling through downstream pathways, resulting in increased survival, invasiveness, and tumorigenicity (Wang et al. 2006).

HER2 amplification does not appear to coincide with HER2 mutation (Buttitta et al. 2006; Stephens et al. 2004). Unlike in breast cancer, there is currently no role for HER2 amplification as a prognostic or predictive marker in NSCLC.

In the vast majority of cases, HER2 mutations are non-overlapping with other oncogenic mutations found in NSCLC (e.g., EGFR mutations, ALK rearrangements, etc.).

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. HER2 (ERBB2) in Non-Small Cell Lung Cancer (NSCLC). My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/erbb2/ (Updated June 18).

Last Updated: June 18, 2015

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