Alterations in PD-L1 Expression Associated with Acquisition of Resistance to ALK Inhibitors in ALK-Rearranged Lung Cancer
- Author:
Su Jung KIM
1
;
Soyeon KIM
;
Dong Wan KIM
;
Miso KIM
;
Bhumsuk KEAM
;
Tae Min KIM
;
Yusoo LEE
;
Jaemoon KOH
;
Yoon Kyung JEON
;
Dae Seog HEO
Author Information
- Publication Type:Original Article
- Keywords: Anaplastic lymphoma kinase; Lung neoplasms; Drug resistance; B7-H1 antigen
- MeSH: Antigens, CD274; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Cell Line; Drug Resistance; Flow Cytometry; Gene Expression; Humans; Immunohistochemistry; Lung Neoplasms; Lung; Lymphoma; Parents; Phosphotransferases; Polymerase Chain Reaction; RNA, Messenger; Sequence Analysis, RNA
- From:Cancer Research and Treatment 2019;51(3):1231-1240
- CountryRepublic of Korea
- Language:English
- 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.
