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, Po Lin Lin, Yao Chen Wang, De Wei Wu, Chi Yi Chen, Huei Lee

研究成果: 雜誌貢獻文章

7 引文 (Scopus)

摘要

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 mutationindependent TKI resistance in NSCLC cells via upregulation of YAP1 expression.
原文英語
頁(從 - 到)4637-4646
頁數10
期刊Oncotarget
9
發行號4
DOIs
出版狀態已發佈 - 一月 1 2018

指紋

Non-Small Cell Lung Carcinoma
Protein-Tyrosine Kinases
Up-Regulation
Mutation
Gene Expression
Neoplasms
Pyocyanine
Tumor Escape
erbB-1 Genes
Messenger RNA
Acetylcysteine
Inhibitory Concentration 50
Cell Survival
Ligands
Therapeutics

ASJC Scopus subject areas

  • Oncology

引用此文

PD-L1 confers resistance to EGFR mutation-independent tyrosine kinase inhibitors in non-small cell lung cancer via upregulation of YAP1 expression. / Tung, Jai Nien; Lin, Po Lin; Wang, Yao Chen; Wu, De Wei; Chen, Chi Yi; Lee, Huei.

於: Oncotarget, 卷 9, 編號 4, 01.01.2018, p. 4637-4646.

研究成果: 雜誌貢獻文章

Tung, Jai Nien ; Lin, Po Lin ; Wang, Yao Chen ; Wu, De Wei ; Chen, Chi Yi ; Lee, Huei. / PD-L1 confers resistance to EGFR mutation-independent tyrosine kinase inhibitors in non-small cell lung cancer via upregulation of YAP1 expression. 於: Oncotarget. 2018 ; 卷 9, 編號 4. 頁 4637-4646.
@article{ad932bcdbf4d4271a8bab4a7ac0ff239,
title = "PD-L1 confers resistance to EGFR mutation-independent tyrosine kinase inhibitors in non-small cell lung cancer via upregulation of YAP1 expression",
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 mutationindependent TKI resistance in NSCLC cells via upregulation of YAP1 expression.",
keywords = "NSCLC, PD-L1, TKI, YAP1",
author = "Tung, {Jai Nien} and Lin, {Po Lin} and Wang, {Yao Chen} and Wu, {De Wei} and Chen, {Chi Yi} and Huei Lee",
year = "2018",
month = "1",
day = "1",
doi = "10.18632/oncotarget.23161",
language = "English",
volume = "9",
pages = "4637--4646",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals LLC",
number = "4",

}

TY - JOUR

T1 - PD-L1 confers resistance to EGFR mutation-independent tyrosine kinase inhibitors in non-small cell lung cancer via upregulation of YAP1 expression

AU - Tung, Jai Nien

AU - Lin, Po Lin

AU - Wang, Yao Chen

AU - Wu, De Wei

AU - Chen, Chi Yi

AU - Lee, Huei

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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 mutationindependent TKI resistance in NSCLC cells via upregulation of YAP1 expression.

AB - 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 mutationindependent TKI resistance in NSCLC cells via upregulation of YAP1 expression.

KW - NSCLC

KW - PD-L1

KW - TKI

KW - YAP1

UR - http://www.scopus.com/inward/record.url?scp=85040450372&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85040450372&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.23161

DO - 10.18632/oncotarget.23161

M3 - Article

AN - SCOPUS:85040450372

VL - 9

SP - 4637

EP - 4646

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 4

ER -