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.