The Second Military Medical University published new results in lung cancer research

Recently, researchers from the Second Military Medical University, East China Normal University, Third Xiangya Hospital of Central South University and Austin University of Texas, published in the American Journal of Oncology, Oncotarget, entitled "Inhibition of non-small cell lung cancer (NSCLC). Growth by a novel small molecular inhibitor of EGFR". In this study, the researchers screened a chemical library of new compounds synthesized in the laboratory and identified a new compound called WB-308. It is pointed out that WB-308 can be used as an ideal substitute for gefitinib and has potential application value in the clinical treatment of non-small cell lung cancer. Although researchers have conducted numerous clinical trials aimed at improving patient survival, lung cancer remains the leading cause of cancer-related mortality in men and women worldwide. There are two main types of lung cancer; one is non-small cell lung cancer (NSCLC; 80% of all lung cancer), including adenocarcinoma, squamous cell carcinoma, large cell carcinoma; the other type is small cell lung cancer, which shows neuroendocrine feature. Further reading: "Cancer": a new biomarker for head and neck cancer and non-small cell lung cancer. According to the latest report, the average survival rate of non-small cell lung cancer is only 16%. More than half of lung cancer cases were diagnosed after metastasis, with a median survival time of 8 months. About 80% of lung cancer cases are non-small cell lung cancer (NSCLC), which is usually diagnosed in the advanced stage. Regarding lung cancer mortality, 80% to 90% of cases are related to metastasis, and one of the most common cases is bone metastasis. In lung cancer bone metastasis, the most common target organ is the spine, which has more serious consequences for the patient's recovery rate and quality of life. There is increasing evidence that epidermal growth factor receptor (EGFR) plays a key role in tumorigenesis, drug resistance, relapse, and metastasis of various cancers. As one of the most common cell surface receptors for the extracellular protein ligand epidermal growth factor family (EGF family), the epidermal growth factor receptor belongs to the ErbB receptor family. Downstream signaling proteins are involved in a variety of signal transduction pathways, such as the MAPK, AKT, ERK1/2 and JNK pathways, triggered by EGFR autophosphorylation. In addition, they are associated with tumorigenesis based on their carcinogenic effects on DNA synthesis and their ability to promote cell proliferation. At the same time, genetic mutations that cause EGFR overexpression or overactivity are also associated with many cancers, including lung cancer, especially non-small cell lung cancer. Given that EGFR is one of the most common mutations in non-small cell lung cancer, EGFR has been recognized as an important target for the treatment of non-small cell lung cancer. At the same time, Gefitinib is considered to be a major selective EGFR tyrosine kinase inhibitor (TKI) for the treatment of non-small cell lung cancer, which acts by inhibiting EGFR oncogenic signaling. Drug gefitinib resistance is mainly due to mutations that occur within the EGFR kinase domain. Since Paez JG initially reported that EGFR-associated mutations can alter the effects of drug therapy, several studies have revealed other molecular mechanisms of drug resistance. Among them, EGFR-TKIs mutations that alter drug sensitivity usually occur in exons 18-21, 49% of which contain exon 19 deletion mutations, and 45% of these EGFR mutations include point mutation L858R of exon 21. These two types of EGFR mutations increase EGFR kinase activity, leading to increased sensitivity of NSCLC patients to clinical treatment of EGFR-TKIs. In addition, not all mutations lead to increased therapeutic sensitivity. For example, gene mutations including insertion of exon 20 confer resistance to EGFR-TKIs. Nearly half of patients with drug-resistant NSCLC have a T790M mutation in exon 20 of EGFR, which is considered to be a major cause of drug resistance. Secondary mutations in T790M in EGFR are also associated with drug resistance and MET amplification. Most mutations, except for T790M or Met amplification, can be eliminated by appropriate selection and combination of second-generation tyrosine kinase inhibitors such as erlotinib and Afatinib. However, there is currently no effective TKI available for non-small cell lung cancer with T790M and MET amplification mutations. Therefore, the development of new small molecules targeting EGFR is of great significance to overcome chemotherapy resistance in the treatment of lung cancer, especially lung cancer. In this study, the researchers screened a chemical library of new compounds synthesized in the laboratory and identified a new compound called WB-308. WB-308 is a potent inhibitor that is effective against wild-type and mutant EGFR kinase activities, which in turn exhibits surprising non-small cell lung anticancer effects. Moreover, these results indicate that WB-308 is unique in that its cytotoxicity is diminished when compared to existing EGFR inhibitory compounds such as gefitinib. In summary, the current WB-308 preclinical study conducted by the research team showed that WB-308 acts similarly to gefitinib and impairs EGFR kinase activity, thereby inhibiting cell growth in non-small cell lung cancer. In addition, mouse models indicate that systemic administration of WB-308 prevents lung cancer cell xenograft models, especially in patient-derived xenograft mouse models. The study concluded that WB-308 can be an ideal substitute for gefitinib and has potential applications in the clinical treatment of NSCLC.

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