Lung cancer is a malignant tumor from the trachea, bronchus, and lung. As one of the most common tumors, its incidence is second only to breast cancer, and the mortality rate is the highest among all tumors, which seriously threatens human health [1]. Lung cancer comprises Small-cell lung cancer (SCLC) and Non-small-cell lung cancer (NSCLC); NSCLC includes adenocarcinoma, squamous carcinoma, adenosquamous carcinoma, large-cell carcinoma, and other types. Multiple risk factors, including smoking, industrial exposure, air pollution, and oncogenic driver mutations, can induce lung cancer [2], [3], [4]. Across oncogenic driver mutations, epidermal growth factor receptor (EGFR), also known as HER1 or ErbB1, is one of the ErbB receptor tyrosine kinase family [5]. Its mutations activate Ras-Raf-MAPK, PI3K-AKT, and JAK2-STAT3 signaling, resulting in cell proliferation, angiogenesis, and metastasis [6], [7]. The most widely used therapy targeting EGFR mutations in NSCLC is EGFR tyrosine kinase inhibitors (EGFR-TKIs) treatment. EGFR-TKIs inhibit EGFR kinase activity by competing for ATP-binding sites on the receptor and inducing the production of inactive homo- or heterodimers, thereby inhibiting tumor growth [8], [9]. The standard first-line treatment for NSCLC patients with EGFR-exon 19 deletions or L858R (a mutation in exon 21) is gefitinib, erlotinib, or afatinib. However, NSCLC patients with EGFR mutations develop resistance to EGFR-TKIs; the EGFR-T790M mutation is one of the most common resistant mutations to first-generation and second-generation EGFR-TKIs. The third-generation EGFR-TKIs, such as Osimertinib and Rociletinib, can efficiently overcome the EGFR-T790M mutation. Unfortunately, NSCLC patients with EGFR-T790M mutation may develop novel resistance to Osimertinib/ Rociletinib during treatment; EGFR-C797S is an acquired drug resistance mutation in the patients [10], [11], [12]. Meanwhile, the discovery of the fourth-generation EGFR TKIs has been ongoing.

However, new EGFR mutations, such as L792H and G796R, are expected to occur and may affect the sensitivity of the next generation of EGFR-TKIs, leading to novel drug resistance [13], [14]. Searching for new targets of EGFR to overcome resistance to EGFR-TKIs caused by novel EGFR mutations is still a significant problem. An in-depth understanding of the regulatory mechanisms of EGFR is essential to overcome its drug resistance. EGFR is a receptor-type kinase, and its kinase activity is closely related to its phosphorylation [15], [16]. In recent years, increasing evidence shows that the kinase activity of EGFR is also affected by many different post-translational modifications (PTMs). In this review, we discuss the effects of EGFR and EGFR-TKIs in NSCLC, focusing on the various PTMs of EGFR. The design of drugs targeting EGFR based on multiple modification sites can provide new targets and effectively avoid resistance mutations against its phosphorylated kinase active sites, which may become potential targets. In addition, the combination of EGFR-TKIs with some post-translational modification inhibitors may exert better therapeutic effects.