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Alterations in PD-L1 expression associated with acquisition of resistance to ALK inhibitors in ALK-rearranged lung cancer

Cited 7 time in Web of Science Cited 8 time in Scopus
Authors
Kim, Su-Jung; Kim, Soyeon; Kim, Dong-Wan; Kim, Miso; Keam, Bhumsuk; Kim, Tae Min; Lee, Yusoo; Koh, Jaemoon; Jeon, Yoon Kyung; Heo, Dae Seog
Issue Date
2019-07
Citation
Cancer Research and Treatment, Vol.51 No.3, pp.1231-1240
Keywords
Anaplastic lymphoma kinaseLung neoplasmsDrug resistanceB7-H1 antigen
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-naive 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-naive 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.
ISSN
1598-2998
URI
http://hdl.handle.net/10371/165220
DOI
https://doi.org/10.4143/crt.2018.486
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College of Medicine/School of Medicine (의과대학/대학원)Cancer Research Institute (암연구소)Journal Papers (저널논문_암연구소)
College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
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