Epidermal growth factor receptor and Programmed cell death protein 1 axis (EGFR–PD-1 axis) (EGFR–PD-1 axis)

The Epidermal growth factor receptor and Programmed cell death protein 1 axis (EGFR–PD-1 axis) represents a critical intersection between oncogenic driver signaling and immune checkpoint-mediated immunosuppression in the tumor microenvironment [PMID: 27117176]. EGFR activation, frequently driven by mutations or overexpression in malignancies such as non-small cell lung cancer (NSCLC), has been shown to upregulate the expression of Programmed Death-Ligand 1 (PD-L1) on tumor cells through intracellular pathways like PI3K/AKT and MEK/ERK [PMID: 30111015]. This upregulation facilitates immune evasion by engaging the PD-1 receptor on infiltrating T cells, leading to functional exhaustion and reduced anti-tumor surveillance. Therapeutic strategies targeting this axis involve the combination of EGFR tyrosine kinase inhibitors (TKIs) or monoclonal antibodies with PD-1/PD-L1 inhibitors to achieve a dual effect: direct suppression of tumor growth and restoration of the immune response [PMID: 31570584]. However, clinical application is complicated by significant safety risks, most notably an increased incidence of severe interstitial lung disease (ILD) observed in combination trials like TATTON, which evaluated osimertinib plus durvalumab [PMID: 32014439]. Consequently, current research focuses on identifying optimal sequencing of therapies and developing bispecific antibodies to safely exploit this axis while minimizing overlapping toxicities [PMID: 34294465].

Other names

EGFR-PD-L1 axisEGFR/PD-1 signaling pathwayEGFR-mediated immune escape axisEGFR-PD-1 crosstalk

The mechanism involves the concurrent inhibition of the Epidermal Growth Factor Receptor (EGFR) to block downstream proliferative signaling (PI3K/AKT and MAPK pathways) and the Programmed Cell Death Protein 1 (PD-1) or its ligand (PD-L1) to prevent T-cell exhaustion and reactivate the host's anti-tumor immune response [PMID: 31570584, 27117176].