PD-L1 confers resistance to EGFR mutation-independent tyrosine kinase inhibitors in non-small cell lung cancer via upregulation of YAP1 expression
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Jai-Nien Tung1,*, Po-Lin Lin2,*, Yao-Chen Wang3, De-Wei Wu2, Chi-Yi Chen4 and Huei Lee2
1Department of Neurosurgery, Tungs’ Taichung MetroHarbor Hospital, Taichung, Taiwan
2Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan
3Department of Internal Medicine, Chung Shan Medical University and Hospital, Taichung, Taiwan
4Department of Surgery, Chung Shan Medical University and Hospital, Taichung, Taiwan
*These authors contributed equally to this work
Huei Lee, email: [email protected]
Keywords: PD-L1; TKI; YAP1; NSCLC
Received: August 30, 2017 Accepted: November 16, 2017 Published: December 08, 2017
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.
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