GENE EXPRESSION C ARTOON TRIAL

Therefore, the identification of new therapeutic methods or agents for the treatment of EGFR-TKI resistant lung cancer is imperative. Among the above mechanisms, high-level MET amplification (11–26%), HGF secretion and MET overexpression were frequently detected in EGFR-TKIs resistant NSCLC, especially acquired third generation EGFR-TKIs resistance, which indicate that the (MET)/hepatocyte growth factor (HGF) pathway becomes an important resistant mechanism especially in third-generation EGFR-TKIs resistant NSCLC. Multiple resistant mechanisms have been identified, including the activation of c-MET signal pathway, MET amplification, hepatocyte growth factor (HGF) and MET overexpression], human epidermal growth factor receptor 2 (HER2) amplification, and EGFR C797S, L792H and G796R mutations. Although third-generation EGFR-TKIs could overcome EGFR mutation threonine 790 (T790M) resistance and are becoming the new first-line standard in EGFR mutant non-small cell lung cancer (NSCLC), acquired resistance is virtually inevitable. Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), which are classic small molecule inhibitors used in targeted treatments, have been shown to prolong the survival time of patients with tumours harboring EGFR-activating mutations from less than 1 year to approximately 20–30 months. Lung cancer is the most common cancer and a leading cause of death from cancer in men and women in the United States. HGF, MET-amplification, and EGFR-T790M upregulate PD-L1 expression in NSCLC and promote the immune escape of tumor cells through different mechanisms. Both MAPK and PI3K pathways were involved in the three types of resistance mechanism-induced PD-L1 overexpression, whereas the NF-kappa B pathway was only involved in T790M-induced PD-L1 expression. Moreover, the above three resistant mechanisms increased PD-L1 expression and attenuated activation and cytotoxicity of lymphocytes in vitro and in vivo, and downregulation of PD-L1 partially restored the cytotoxicity of lymphocytes. Positive correlations were found among PD-L1, c-MET, and HGF, based on TCGA datasheets and paired NSCLC specimens. PD-L1-deleted EGFR-TKIs sensitive and resistant cells were used to evaluate the immune escape ability of tumors in mice xenograft models.

EGFR-TKI resistant NSCLC cells with three well-known mechanisms, c-MET amplification, hepatocyte growth factor (HGF), and EGFR-T790M, were investigated to determinate PD-L1 expression status and immune escape ability.

The correlation among PD-L1, c-MET, and HGF was analyzed based on TCGA datasheets and paired NSCLC specimens before and after acquired EGFR-TKI resistance. Therefore, the determination of status and regulatory mechanisms of PD-L1 in EGFR mutant NSCLC before and after acquired EGFR-TKIs resistance are meaningful.

GENE EXPRESSION C ARTOON TRIAL

The ATLANTIC trial reported that higher PD-L1 expression in tumors was involved in a higher objective response in patients with EGFR + /ALK + non-small cell lung cancer (NSCLC), indicating the possibility of anti-PD-1/PD-L1 therapy as a third-line (or later) treatment for advanced NSCLC.

Gene expression c artoon