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Cancer Research and Treatment > Accepted Articles
doi: https://doi.org/10.4143/crt.2018.486    [Accepted]
Alterations in PD-L1 Expression Associated with Acquisition of Resistance to ALK Inhibitors in ALK-Rearranged Lung Cancer
Su-Jung Kim1, Soyeon Kim1, Dong-Wan Kim1,2,3, Miso Kim1,2, Bhumsuk Keam1,2, Tae Min Kim1,2, Yusoo Lee1, Jaemoon Koh4, Yoon Kyung Jeon4,5, Dae Seog Heo1,2,3
1Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
2Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
3Department of Internal Medicine, Seoul National University, Seoul, Korea
4Department of Pathology, Seoul National University Hospital, Seoul, Korea
5Department of Pathology, Seoul National University, Seoul, Korea
Correspondence  Dong-Wan Kim ,Tel: 82-2-2072-2995 , Fax: 82-2-764-2199, Email: kimdw@snu.ac.kr
Received: August 30, 2018;  Accepted: December 27, 2018.  Published online: December 31, 2018.
*Su-Jung Kim and Soyeon Kim contributed equally to this work.
ABSTRACT
Purpose
The purpose of this study was to evaluate the relationships between the resistance of anaplastic lymphoma kinase (ALK)‒positive non-small cell lung cancer (NSCLC) to ALK inhibitors and the programmed cell death-1/programmed cell death–ligand 1 (PD-L1) pathway, we evaluated alterations in PD-L1 following acquisition of resistance to ALK inhibitors in ALK-positive lung cancer.
Materials and Methods
We established ALK inhibitor-resistant cell lines (H3122CR1, LR1, and CH1) by exposing the parental H3122 ALK-translocated NSCLC cell line to ALK inhibitors. Then, the double-resistant cell lines H3122CR1LR1 and CR1CH1 were developed by exposing the H3122CR1 to other ALK inhibitors. We compared the alterations in PD-L1 expression levels using western blotting, flow cytometry, and quantitative polymerase chain reaction. We also investigated gene expression using RNA sequencing. The expression of PD-L1 in the tumors from 26 ALK-positive metastatic NSCLC patients (11 ALK inhibitor-naïve and 15 ALK inhibitor-resistant patients) was assessed by immunohistochemistry and analyzed.
Results
PD-L1 was expressed at higher levels in ALK inhibitor-resistant cell lines than in the ALK inhibitor-naïve parental cell line at the total protein, surface protein, and mRNA levels. Furthermore, PD-L1 expression in the double-resistant cell lines was much higher than that in the single resistant cell lines. RNA sequencing demonstrated that expression of immune-related genes were largely involved in ALK inhibitor resistance. The mean value of the PD-L1 H-score was 6.5 pre-treatment and 35.0 post-treatment, and the fold difference was 5.42 (p=0.163).
Conclusion
PD-L1 expression increased following acquisition of ALK inhibitor resistance in ALK-positive NSCLC cell lines and tumors.
Key words: Anaplastic lymphoma kinase, Lung neoplasms, Drug resistance, B7-H1 antigen
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