*September 2021*
Note: This is a deep dive into the different types of EGFR NSCLC and how EGFR TKIs (targeted therapies) work, how resistance occurs, and the mechanisms of drug resistance and therapeutic strategies. It’s a good article to keep in your back pocket for reference after progression on osimertinib (Tagrisso).
Molecular targeted therapy has been reported to have fewer adverse effects, and offer a more convenient route of administration, compared with conventional chemotherapy. With the development of sequencing technology, and research on the molecular biology of lung cancer, especially whole-genome information on non-small cell lung cancer (NSCLC), various therapeutic targets have been unveiled. Among the NSCLC-driving gene mutations, epidermal growth factor receptor (EGFR) mutations are the most common, and approximately 10% of Caucasian, and more than 50% of Asian, NSCLC patients have been found to have sensitive EGFR mutations. A variety of targeted therapeutic agents for EGFR mutations have been approved for clinical applications, or are undergoing clinical trials around the world. This review focuses on: the indications of approved small molecular kinase inhibitors for EGFR mutation-positive NSCLC; the mechanisms of drug resistance and the corresponding therapeutic strategies; the principles of reasonable and precision molecular structure; and the drug development discoveries of next-generation inhibitors for EGFR.
Lung cancer is a serious threat to human health [1]. A global cancer report published by the World Health Organization (WHO) in 2020 reports that lung cancer is still the most common and fatal cancer, and it affects both men and women [2]. Lung cancer patients not only experience great psychological pressure, but also suffer severe pain due to the disease. Moreover, the high cost of treatment presents a great burden to both individuals and society [3].
The goal of advanced lung cancer treatment is to prolong the overall survival time of patients and to improve their quality of life [4]. Chemotherapy is one approach that kills cancer cells, and it can be administered orally or by injection. Platinum-based chemotherapy in combination with other cytotoxic drugs for 4–6 cycles is the current routine treatment. However, chemotherapy is not recommended for elderly patients with weak conditions, cachexia, serious dysfunction of the heart, liver, or kidney, or poor bone marrow function. With the advanced improvement of sequencing technology and in-depth research on the molecular biology of lung cancer, especially whole-genome sequencing, targeted therapy for solid tumors has rapidly developed. This has brought good news for, especially advanced, non-small-cell lung cancer (NSCLC) patients.
With the advancements in modern medicine, the diagnosis of, and therapy for, NSCLC have entered the era of “precision medicine”, facilitating more accurate diagnosis and treatment. According to the latest National Comprehensive Cancer Network (NCCN) guidelines for NSCLC (3rd Edition, 2021), the genes with driver mutations include: epidermal growth factor receptor (EGFR); anaplastic lymphoma kinase (ALK), c-ros oncogene 1 receptor tyrosine kinase (ROS1); human epidermal growth factor receptor 2 (HER2); mesenchymal to epithelial transition factor (MET); v-raf murine sarcoma viral oncogene homolog B1 (BRAF); Kirsten rat sarcoma (KRAS); rearrangement during transfection (RET); and neurotrophic tyrosine receptor kinase (NTRK) [5]. Individualized molecular targeted therapy for driver genes has been reported to block the key signaling pathway of tumor cell growth and proliferation, inhibit tumor cell proliferation, and selectively kill tumor cells by applying highly specific molecules targeted to the definite (or highly expressed) biomarkers of the tumor cells [6]. In recent decades, a variety of targeted therapeutic agents have been approved for clinical applications, or are undergoing clinical trials, that have become the standard treatment for advanced lung cancer because of their significant efficacy and safety.
Among the driver mutations of NSCLC, EGFR mutation is the most conventional driver gene in NSCLC, and approximately 10% of Caucasian, and more than 50% of Asian, NSCLC patients have been found to have sensitive EGFR mutations [7]. EGFR is reported as a subtype of the erythroblastosis oncogene B (ErbB)/human epidermal growth factor receptor (HER) family, which is also named ErbB1 (EGFR/HER1) [8,9]. As a transmembrane tyrosine kinase receptor, activated EGFR was reported to facilitate signal transduction in critical pathways of tumorigenesis [10,11]. Since the 1990s, various drug development strategies for the inhibition of overactivated EGFR have been carried out. The EGFR-targeted drugs for NSCLC that are available on the market are classified into two major categories: EGFR monoclonal antibody drugs that block the binding of extracellular ligand receptors, and small molecule chemical kinase inhibitors that inhibit the intracellular ATP binding site of tyrosine kinase [12]. Currently, the approved EGFR monoclonal antibodies are nimotuzumab and necitumumab, which are applied in combination with chemotherapy drugs in the clinic [13,14,15]. Treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is considered more convenient, and can significantly prolong the survival time of patients, compared with the expensive therapeutic regimen of antibodies. In this review, we will focus on the indications of approved inhibitors for EGFR mutation-positive advanced NSCLC, the mechanisms of drug resistance and the corresponding therapeutic strategies, as well as the principles of reasonable and precision molecular structure for the discovery of next-generation EGFR-TKIs in order to accelerate anticancer drug discovery.
