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Biochem Biophys Res Commun. 2017 Sep 16;491(2):493-499. doi: 10.1016/j.bbrc.2017.07.007. Epub 2017 Jul 3.

Hippo effector YAP directly regulates the expression of PD-L1 transcripts in EGFR-TKI-resistant lung adenocarcinoma.

Author information

1
Division of Pulmonology, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon 35015, South Korea.
2
Department of Pathology, College of Medicine, Chungnam National University, Daejeon 35015, South Korea.
3
National Creative Research Center for Cell Division and Differentiation, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, South Korea.
4
Chungnam National University School of Medicine, Daejeon, South Korea. Electronic address: nprc26@gmail.com.
5
Division of Pulmonology, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon 35015, South Korea. Electronic address: liansalt@daum.net.
6
Division of Pulmonology, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon 35015, South Korea. Electronic address: universe7903@gmail.com.

Abstract

Developments of EGFR-TKI and immunotherapy targeting the PD1/PD-L1 pathway are considered most important medical breakthroughs in lung cancer treatment. Nowadays, 3rd generation EGFR TKI is widely used for T790M positive 1st and 2nd EGFR-TKI resistant lung cancer patients. Immunotherapy is powerful option for lung cancer patients without drug targets and chemotherapy resistant patients. It also has changed the concept of conventional anti-cancer therapy in the point of regulating tumor microenvironment. There are many studies linking these two important pathways. Recent studies demonstrated that PD-L1 expression is significantly correlated to the mutation status of EGFR, and activation of EGFR signaling can also induce the expression of PD-L1. However, the real linker between PD-L1 and EGFR signaling remains to be revealed. Our previous study revealed that the Hippo pathway effector YAP confers EGFR-TKI resistance in lung adenocarcinoma, and inhibition of YAP restores sensitivity to EGFR-TKIs. Thus, we examined whether PD-L1 is relevant, in terms of conferring EGFR-TKI resistance and whether YAP directly regulates the expression of PD-L1 in this context. First, we compared the expression levels of PD-L1 and YAP between EGFR-TKI-resistant PC9 cells and the parental PC9 adenocarcinoma cells. The expression levels of both YAP and PD-L1 were markedly higher in the EGFR-TKI-resistant cells compared to the parental cells, suggesting differential expression pattern between two cell types. YAP knockdown significantly decreased the expression of PD-L1 in the EGFR-TKI-resistant cells, while YAP overexpression increased the expression of PD-L1 in the parental PC9 cells. Then, our results revealed that YAP regulates the transcription of PD-L1, and the YAP/TEAD complex binds to the PD-L1 promoter. Surprisingly, knockdown of PD-L1 was sufficient to decrease cell proliferation and wound healing in the EGFR-TKI-resistant PC9 cells. These data suggest a PD1-independent oncogenic function of PD-L1. The Hippo effector YAP plays a crucial role in linking the PD-L1 and EGFR-TKI resistance by directly regulating the expression of PD-L1 in lung cancer. Targeting PD-L1 directly or via YAP could provide an effective therapeutic strategy for EGFR-TKI-resistant lung adenocarcinoma.

KEYWORDS:

Adenocarcinoma; EGFR; Immunotherapy; PD-L1; YAP1

PMID:
28684311
DOI:
10.1016/j.bbrc.2017.07.007
[Indexed for MEDLINE]

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