Figure 3. Cytokines in TIME of EGFR mutant lung cancer.
EGFR-TKIs can induce PD-L1 protein degradation through the GSK3 β pathway and ubiquitin protease pathway, which contributes to T cell activation. EGFR mutation can up regulate amphiregulin (AREG) and AREG maintains the Treg cell suppressive function via the EGFR/GSK-3β/Foxp3 axis. Axl kinase, genes encoding immune checkpoint molecules (CD274, CTLA4), chemokine receptors (CXCR4, CXCR6), or chemokines (CXCL16) are overexpression in EGFR-TKI resistant NSCLC. Overexpression of hepatocyte growth factor (HGF) induces EMT through the HGF-MET pathway, resulting in EGFR-TKIs resistance. PD-L1 induces EMT through the TGF-β/Smad3 pathway. Activation of the TGF-β/Smad2 pathway can also induce EMT by increasing the expression of CXCR4. Furthermore, TGF-β can induce EMT and EGFR-TKIs resistance by increasing the expression of PCKα, activating the Akt-ERK pathway, increasing the expression of MIG6, and decreasing the expression of PTEN. Adrenergic β2 receptor can induce EGFR-TKIs resistance by increasing the expression of IL-6. RNF25 promoted EGFR-TKIs resistance by inducing ERK reactivation through the expression of IL6 via the NK-κB signal pathway. ILK, SHP, SPP1, IGF1R are highly expressed in EGFR-TKIs resistant NSCLC. CXCR7 can promote EGFR-TKIs resistance by EMT of tumor cells through activation of MAPK-ERK pathway via β-arrestin.