PD-L1 confers resistance to EGFR mutation-independent tyrosine kinase inhibitors in non-small cell lung cancer via upregulation of YAP1 expression

// Jai-Nien Tung 1, * , Po-Lin Lin 2, * , Yao-Chen Wang 3 , De-Wei Wu 2 , Chi-Yi Chen 4 and Huei Lee 2 1 Department of Neurosurgery, Tungs’ Taichung MetroHarbor Hospital, Taichung, Taiwan 2 Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan 3 Department of Internal Medicine, Chung Shan Medical University and Hospital, Taichung, Taiwan 4 Department of Surgery, Chung Shan Medical University and Hospital, Taichung, Taiwan * These authors contributed equally to this work Correspondence to: Huei Lee, email: hl@tmu.edu.tw Keywords: PD-L1; TKI; YAP1; NSCLC Received: August 30, 2017      Accepted: November 16, 2017      Published: December 08, 2017 ABSTRACT Programmed death ligand (PD-L1) expression was associated with tumor immune escape and subsequent poor prognosis in non-small cell lung cancer (NSCLC). This expression was higher in patients with EGFR-mutated NSCLC tumors than in those with EGFR-wild-type (WT) NSCLC tumors. We therefore hypothesized that poor prognosis mediated by higher PD-L1 may be partially through conferring resistance to tyrosine kinase inhibitor (TKI) in NSCLC regardless of EGFR mutation. The change in PD-L1 expression following gene manipulation corresponded with changes in expression of HIF-1α and YAP1. The expression of HIF-1α and YAP1 was concomitantly decreased by PD-L1 silencing or by ROS scavenger treatment (N-acetylcysteine, NAC); however, a ROS inducer treatment (pyocyanin) completely reversed the decreased expression of both genes in EGFR-mutated and -wild-type (WT) NSCLC cells. The MTT assay indicated that the inhibitory concentration of gefitinib yielding 50% cell viability (IC50) depended on PD-L1-mediated YAP1 expression. Mechanistic studies indicated that upregulation of YAP1 by PD-L1 might be responsible for EGFR mutation-independent TKI resistance via the ROS/HIF-1α axis. An unfavorable TKI response was more common in patient tumors with high PD-L1 or YAP1 mRNA expression than in patient tumors with low mRNA expression of these genes. In conclusion, PD-L1 might confer EGFR mutation-independent TKI resistance in NSCLC cells via upregulation of YAP1 expression.