Why is EGFR key of lung cancer?

EGFR mutation in NSCLC

Lung cancer is a major cause of cancer-related death in the world and can be classified into NSCLC (Non-small-cell lung carcinoma) and SCLC (small-cell lung carcinoma). NSCLC is the major type of lung cancer which comprises around 80% of all lung cancers. 

EGFR is a key biomarker used for cancer diagnostics and therapy in NSCLC. Genetic mutation of the EGFR occurs in approximately 20% of patients with lung adenocarcinomas in Caucasians and 40% in East Asians. Especially these EGFR mutations are more frequently found in women, never smokers, patients from East Asia [1-4]. Moreover, Recent study results indicated that different races showed different EGFR mutation frequencies (Fig.1). [5] 

Classification of EGFR somatic mutation in NSCLC

EGFR regulates epithelial tissue development and homeostasis. Downstream of EGFR signaling regulates diverse biological processes including cell proliferation, differentiation, and cell survival. However, abnormal function of EGFR, when acting as the oncogene, these mutations are mostly observed in lung and breast cancer. [6] Among the EGFR mutation in lung cancer patients, deletions in exon 19 and arginine for leucine substitution at amino acid 858 (L858R) in exon 21, most frequently found in all EGFR mutations. Deletion mutants in exon 19 and L858R, consist of approximately 85% of observed EGFR mutations in NSCLC. Except 19 del and L85R mutations, the remaining 15% of rare EGFR mutations include single amino acid point mutations, deletions in exon, and insertions in exons 18–25 of the EGFR gene (Fig.2). [6,7,8]

The most common mutations are L858R and exon 19 deletions which respectively account for 41% and 44% of all EGFR mutations. Deletion of exon 19 has been reported to increase EGFR autophosphorylation, and promote cell survival by selectively activating AKT and STAT pathways. L858R and exon 19 deletions mutants destabilize the inactive conformation of the receptor and increase receptor dimerization and activity compared to WT (Fig.3).

Except for L858R and 19 del mutations, G719X and exon 20 insertions are the next most common EGFR mutations in NSCLC. Single amino acid replacement mutations called G719X, which consist with G719S, G719A, G719C, and G719D substitutions, and these mutations account for approximately 1.5–3% of all EGFR mutations in NSCLC. Other than L858R and exon 19 deletions mutations, EGFR exon 20 insertions are the next most common EGFR mutation in NSCLC, with frequencies reported at between 4–10% of all observed EGFR mutations. S768I is one of the mutations in exon 20 of the EGFR gene and its frequency is indicated between 0.6–1% of EGFR mutations in NSCLC (Fig. 4). [8,9] 

Moreover, EGFR mutations can provide some information for cancer diagnostics and therapy in NSCLC. Small molecule inhibitors called EGFR TKIs (EGFR-tyrosine kinase inhibitors) often develop a second-site mutation in the threonine residue at position 790, T790M. This mutation is 50% of EGFR-mutant tumors with acquired resistance to erlotinib or gefitinib. [10]

EGFR is commonly over-expressed in various cancers such as NSCLC, colorectal cancer, glioblastoma, pancreatic cancer, and breast cancer. Many cellular mechanisms mediate the hyperactivity of EGFR activity, including common mutations in EGFR extracellular and tyrosine kinase domain, such as L858R, exon 19 deletions, and T90M mutation. These abnormal EGFR regulates downstream pro-oncogenic signaling pathways such as RAS-RAF-MEK-ERK MAPK and PI3K-AKT-mTOR signaling pathways. These pathways control cell proliferation, metabolism, and differentiation but in cancer, abnormal function of these pathways leads to oncogenesis. [6] Thus, as we mentioned EGFR functions that EGFR is important for cancer research, drug discovery, and cancer diagnosis.

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References

[1] R. Rosell, et al., Screening for epidermal growth factor receptor mutations in lung cancer, N. Engl. J. Med. 361 (10) (2009) 958–967.

[2] S.P. D’Angelo, et al., Incidence of EGFR exon 19 deletions and L858R in tumor specimens from men and cigarette smokers with lung adenocarcinomas, J. Clin. Oncol. 29 (15) (2011) 2066–2070.

[3] E.A. Collisson, et al., Comprehensive molecular profiling of lung adenocarcinoma, Nature 511 (7511) (2014) 543–550.

[4] Y. Shi, et al., A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non–small-cell lung cancer of adenocarcinoma histology (PIONEER), J. Thorac. Oncol. 9 (2) (2014) 154–162.

[5] Determining EGFR-TKI sensitivity of G719X and other uncommon EGFR mutations in non-small cell lung cancer: Perplexity and solution (Review), Kaidi Li et al, Oncol Rep, 2017

[6] Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways. Ping Wee, Zhixiang Wang, Cancers (Basel), 2017,17;9(5):5

[7] Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer. 2007 Mar;7(3):169-81. Sharma SV et al.

[8] Rare epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer. Semin Cancer Biol. 2020 Apr;61:167-179. doi: 10.1016/j Harrison PT et al.

[9] Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in non-small cell lung cancer harboring uncommon EGFR mutations: Focus on afatinib. Semin Oncol. 2019 Jun;46(3):271-283. doi: 10.1053/j. Masood A et al.

[10] Targeting EGFR exon 20 insertion mutations in non-small cell lung cancer. Vyse S, et al. Signal Transduct Target Ther. 2019.