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)
Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94115, USA
Department of Thoracic Medicine, Chang Gung Memorial Hospital, Linkou, Taoyuan 33305, Taiwan
School of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(15), 3821; https://doi.org/10.3390/ijms20153821
Received: 28 June 2019 / Revised: 2 August 2019 / Accepted: 2 August 2019 / Published: 5 August 2019
(This article belongs to the Special Issue PD-L1, A Master Regulator of Immunity)
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.