Epidermal growth factor receptor (EGFR): A rising star in the era of precision medicine of lung cancer

Abstract

Lung cancer is a leading cause of cancer mortality worldwide. In tumors, the important role of noncoding RNA regulatory networks has been more and more reveal. EGFR has been identified as an oncogenic driver of NSCLC, especially activating mutations EGFR and its inhibition with specific TKIs can generate dramatic tumor responses. Studies have shown that EGFR plays significant roles in the progression of NSCLC. Subset analysis of the small proportion of patients with EGFR-mutant lung cancer showed a disease-free survival benefit, but was underpowered to detect a survival advantage. Herein, we highlight the progression of EGFR, noncoding RNA, and their roles in carcinogenesis. We also focus on anti-lung cancer drug development and EGFR-related drug resistance.

Keywords: epidermal growth factor receptor (EGFR); lung cancer; noncoding RNA; precision medicine.

Figure 1. EGFR signaling pathway

EGFR is a receptor protein that spans the cell membrane. TKI consists of N lobe and C lobe. EGFR-TKI competes with ATP for inhibition of this site. If the growth factor (ligand) binds to the receptor, it forms an asymmetric dimer. A variety of proteins associated with the phosphorylation of tyrosine, the downstream protein is constantly activated, as shown in chart the RAS-RAF-MAPK pathway and PI3K-AKT pathway.

Figure 2. EGFR mutations and drug-resistant mechanism

As common mutant sites, the mutations of exon18-21 in EGFR are discovered. It's including common mutations and rare mutations. Common mutations are involved deletion mutations in 45 percent of 19 exon, and point mutations of L858R in 40–45 percent of 21 exon. Others are rare mutations. The reason to raise drug-resistant is that it arises new mutations, the most important mutations is T790M in 50 percent. I stands for Mutations associated with drug resistant, II stands for Mutations associated with drug sensitivity.

Figure 3. Timeline of EGFR-related drug development

Figure 4. An illustration representing long noncoding RNAs (lncRNAs) and they involved in EGFR signaling pathway in lung cancer