Epidermal Growth Factor Receptor (EGFR) Pathway, Yes-Associated Protein (YAP) and the Regulation of Programmed Death-Ligand 1 (PD-L1) in Non-Small Cell Lung Cancer (NSCLC)

Abstract

The epidermal growth factor receptor (EGFR) pathway is a well-studied oncogenic pathway in human non-small cell lung cancer (NSCLC). A subset of advanced NSCLC patients (15-55%) have EGFR-driven mutations and benefit from treatment with EGFR-tyrosine kinase inhibitors (TKIs). Immune checkpoint inhibitors (ICIs) targeting the PD-1/PDL-1 axis are a new anti-cancer therapy for metastatic NSCLC. The anti-PD-1/PDL-1 ICIs showed promising efficacy (~30% response rate) and improved the survival of patients with metastatic NSCLC, but the role of anti-PD-1/PDL-1 ICIs for EGFR mutant NSCLC is not clear. YAP (yes-associated protein) is the main mediator of the Hippo pathway and has been identified as promoting cancer progression, drug resistance, and metastasis in NSCLC. Here, we review recent studies that examined the correlation between the EGFR, YAP pathways, and PD-L1 and demonstrate the mechanism by which EGFR and YAP regulate PD-L1 expression in human NSCLC. About 50% of EGFR mutant NSCLC patients acquire resistance to EGFR-TKIs without known targetable secondary mutations. Targeting YAP therapy is suggested as a potential treatment for NSCLC with acquired resistance to EGFR-TKIs. Future work should focus on the efficacy of YAP inhibitors in combination with immune checkpoint PD-L1/PD-1 blockade in EGFR mutant NSCLC without targetable resistant mutations.

Keywords: epidermal growth factor receptor (EGFR); immune checkpoint inhibitors (ICIs); non-small cell lung cancer (NSCLC); programmed death-ligand 1 (PD-L1); tyrosine kinase inhibitor (TKI); yes-associated protein (YAP).

Figure 1

The Epidermal growth factor receptor (EGFR) pathway in non-small cell lung cancer (NSCLC). EGFR kinase domain mutations including exon 19 deletion, L858R and T790M increase kinase activity of EGFR, leading to the hyperactivation of downstream signaling pathways including MAPK, PI3K/Akt/mTOR, and IL-6/JAK/STAT3 which promote tumorigenesis of NSCLC cells. The three generations of EGFR-TKIs differ with respect to how they bind to different EGFR mutations and which EGFR mutations are active or inactive.

Figure 2

PD-1/PD-L1 immune checkpoint in NSCLC. In NSCLC cells, the binding of PD-1 and PD-L1 promotes T-cell tolerance and escape from host immunity. Immunotherapy targeting the PD-1/PD-L1 immune checkpoints has used to treat metastatic NSCLC. Pembrolizumab, nivolumab and cemiplimab are anti-PD-1 inhibitors, and atezolizumab, durvalumab and avelumab are anti-PD-L1 inhibitors.

Figure 3

The EGFR pathway regulates PD-L1 expression in NSCLC. Stimulation of EGF or activation of EGFR kinase domain induced PD-L1 expression may be through the activating Hippo/yes-associated protein (YAP) signaling pathway in human NSCLC cells. Inhibition of EGFR by EGFR-TKIs downregulates PD-L1 expression in human EGFR-driven NSCLC cells.

Figure 4

In EGFR mutant NSCLC without targetable resistant mutations, activation of YAP enhances the downstream genes expression of EGFs, ERBB3, ERBB4, CTGF, and CYR61 to form an autocrine loop and reinforce MAPK signaling pathway to induce cancer progression, drugs resistance, and immune escape. YAP blockade by MEK 1/2, CDK1, CDK9, and YAP-TEAD complex inhibitors in combination with anti-PD-1/PD-L1 ICIs may be a future therapeutic strategy for the treatment of EGFR mutant NSCLC without targetable resistant mutations.