|Table of Contents|

Screening immunotherapy markers and adjuvant drugs for PD-L1 negative patients with non-small cell lung cancer based on network regulation analysis

Journal Of Modern Oncology[ISSN:1672-4992/CN:61-1415/R]

Issue:
2024 15
Page:
2776-2782
Research Field:
Publishing date:

Info

Title:
Screening immunotherapy markers and adjuvant drugs for PD-L1 negative patients with non-small cell lung cancer based on network regulation analysis
Author(s):
KE Yizhong; SHI Lei
The Cancer Hospital of the University of Chinese Academy of Sciences(Zhejiang Cancer Hospital),Institute of Basic Medicine and Cancer(IBMC),Chinese Academy of Sciences,Zhejiang Hangzhou 310022,China.
Keywords:
non-small cell lung cancer; PD-L1; risk ratio regression model; weighted gene co-expression network analysis
PACS:
R734.2
DOI:
10.3969/j.issn.1672-4992.2024.15.013
Abstract:
Objective:To screen potential immunotherapy targets for PD-L1 negative non-small cell lung cancer(NSCLC) patients based on weighted gene co-expression network analysis and identify corresponding small molecule drugs to enhance immunotherapeutic response.Methods:A total of 1 037 NSCLC samples and 108 normal samples were retrieved from the TCGA database,along with 60 NSCLC samples and 9 normal samples from the GEO database.After data normalization,patients with PD-L1 expression levels in the lowest quintile were defined as PD-L1 negative patients,and the differentially expressed genes between the two datasets were used as input for weighted gene co-expression network analysis.Concurrently,a Cox proportional hazards regression model was constructed to evaluate the prognostic impact of high-risk genes.Finally,small molecule drugs targeting the identified risk genes were screened from the DrugBank database and subjected to molecular docking simulations.Results:The COX proportional hazards regression model stratified patients into high-risk and low-risk groups based on the expression levels of six risk genes(CXCL12,GBP1,TGM2,HMOX1,GBP3,C1QB).Significant differences were observed between the two groups in terms of patient survival time,survival status,immune cell proportion,stromal cell proportion,and gene expression(P<0.05).The model achieved AUCs of 0.860 and 0.752 in the test and validation sets,respectively.Furthermore,GBP1 and TGM2 were associated with poorer prognosis in the high-risk group,and were thus identified as the final biomarkers.Four small molecule drugs targeting GBP1 and TGM2 were screened from the drug database and exhibited effective binding.Conclusion:GBP1 and TGM2 may serve as potential biomarkers for immunotherapy in NSCLC,and combination therapy with small molecule drugs targeting these genes could enhance immunotherapeutic response.

References:

［1］BRAY F,LAVERSANNE M,SUNG H,et al.Global cancer statistics 2022：Globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries［J］.CA Cancer J Clin,2024,74(3)：229-263.
［2］SIMBOLO M,BARBI S,FASSAN M,et al.Gene expression profiling of lung atypical carcinoids and large cell neuroendocrine carcinomas identifies three transcriptomic subtypes with specific genomic alterations［J］.Journal of Thoracic Oncology,2019,14(9)：1651-1661.
［3］BALATA H,FONG KM,HENDRIKS LE,et al.Prevention and early detection for NSCLC：Advances in thoracic oncology 2018［J］.Journal of Thoracic Oncology,2019,14(9)：1513-1527.
［4］ZAROGOULIDIS K,ZAROGOULIDIS P,DARWICHE K,et al.Treatment of non-small cell lung cancer(NSCLC)［J］.Journal of Thoracic Disease,2013,5(Suppl 4)：S389-S396.
［5］GAO J,LI HR,JIN C,et al.Strategies to overcome acquired resistance to EGFRTKI in the treatment of non-small cell lung cancer［J］.Clinical and Translational Oncology,2019,21(10)：1287-1301.
［6］SUN C,MEZZADRA R,SCHUMACHER TN.Regulation and function of the PD-L1 checkpoint［J］.Immunity,2018,48(3)：434-452.
［7］ROWSHANRAVAN B,HALLIDAY N,SANSOM DM.CTLA-4：A moving target in immunotherapy［J］.Blood,2018,131(1)：58-67.
［8］WANG JH,CHEN GY.Advances in the study of predictive markers of immunotherapy for non-small cell lung cancer based on PD-1/PD-L1 inhibitors［J］.Modern Oncology，2021，29(10):1822-1825.
［9］VAN DER MAATEN L,HINTON G.Visualizing data using t-SNE［J］.Journal of Machine Learning Research,2008,9(86)：2579-2605.
［10］BREMNES RM,BUSUND LT,KILVR TL,et al.The role of tumor-infiltrating lymphocytes in development,progression,and prognosis of non-small cell lung cancer［J］.Journal of Thoracic Oncology,2016,11(6)：789-800.
［11］MOK TSK,WU YL,KUDABA I,et al.Pembrolizumab versus chemotherapy for previously untreated,PD-L1 expressing,locally advanced or metastatic non-small cell lung cancer(KEYNOTE-042)：A randomised,open-label,controlled,phase 3 trial［J］.The Lancet,2019,393(10183)：1819-1830.
［12］VELCHETI V,SCHALPER KA,CARVAJAL DE,et al.Programmed death ligand-1 expression in non-small cell lung cancer［J］.Laboratory Investigation,2014,94(1)：107-116.
［13］HONKALA AT,TAILOR D,MALHOTRA SV.Guanylate-binding protein 1：An emerging target in inflammation and cancer［J］.Frontiers In Immunology,2020,10：3139-3149.
［14］CHENG L,GOU L,WEI T,et al.Gbp1 promotes erlotinib resistance via PGK1-activated emt signaling in non-small cell lung cancer［J］.International Journal of Oncology,2020,57(3)：858-870.
［15］LI C,CAI J,GE F,et al.TGM2 knockdown reverses cisplatin chemoresistance in osteosarcoma［J］.International Journal of Molecular Medicine,2018,42(4)：1799-1808.
［16］YANG P,YU D,ZHOU J,et al.TGM2 interference regulates the angiogenesis and apoptosis of colorectal cancer via WNT/β-catenin pathway［J］.Cell Cycle,2019,18(10)：1122-1134.
［17］LIU J,LIU Q,ZHANG X,et al.Immune subtyping for pancreatic cancer with implication in clinical outcomes and improving immunotherapy［J］.Cancer Cell International,2021,21(1)：1-14.
［18］ZHANG Q,YI H,YAO H,et al.Artemisinin derivatives inhibit non-small cell lung cancer cells through induction of ROS-dependent apoptosis/ferroptosis［J］.Journal of Cancer,2021,12(13)：4075-4085.

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Last Update: 2024-06-28