"The Multi-Omics Analysis of Key Genes Regulating EGFR-TKI Resistance, Immune Infiltration, SCLC Transformation in EGFR-Mutant NSCLC"

作者全名："Wang, Zhi; Zhang, Lingling; Xu, Wenwen; Li, Jie; Liu, Yi; Zeng, Xiaozhu; Zhong, Maoxi; Zhu, Yuxi"

作者地址："[Wang, Zhi; Zhang, Lingling; Xu, Wenwen; Li, Jie; Liu, Yi; Zeng, Xiaozhu; Zhong, Maoxi; Zhu, Yuxi] Chongqing Med Univ, Affiliated Hosp 1, Dept Oncol, Chongqing 400042, Peoples R China; [Zhu, Yuxi] Chongqing Med Univ, Affiliated Hosp 1, Jinshan Hosp, Dept Oncol, Chongqing 400042, Peoples R China"

通信作者："Zhu, YX (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Dept Oncol, Chongqing 400042, Peoples R China.; Zhu, YX (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Jinshan Hosp, Dept Oncol, Chongqing 400042, Peoples R China."

来源：JOURNAL OF INFLAMMATION RESEARCH

ESI学科分类：IMMUNOLOGY

WOS号：WOS:000751851300004

JCR分区：Q3

影响因子：4.5

年份：2022

卷号：15

期号：　

开始页：649

结束页：667

文献类型：Article

关键词：  bioinformatics analysis; drug resistance; epidermal growth factor receptor; non-small cell lung cancer; small cell lung cancer transformation; immune cell infiltration

摘要："Background: Lung cancer is a high-risk malignancy worldwide. The harboring of epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) makes EGFR-tyrosine kinase inhibitor (EGFR-TKI) an attractive therapeutic option. However, patients usually suffer the primary and secondary resistance to EGFR-TKI. And the molecular alteration is still not fully clear and needs further study. Methods: The GEO database was utilized to find the differentially expressed genes (DEGs) in NSCLC profiles resistant to the 1st or 2nd generation EGFR-TKI. We analyzed the expression and pathway enrichment of hub genes, and the prognosis of EGFR mutant/ wild-type lung adenocarcinoma (LUAD). Moreover, small cell lung cancer (SCLC) and TKI-resistant profiles were used to find common DEGs, and construct miRNA regulatory network. Analysis was performed of hub genes' related immune infiltration, drug sensitivity, and methylation. Further, we analyzed hub gene expression in EGFR-mutant LUAD and paracancerous tissue by qRT-PCR. Results: A total of 107 DEGs were found related to TKI resistance. Eleven hub genes were obtained after visualization, of which 5 hub genes were co-expressed in SCLC with common miRNAs. Lower expression of SPP1 (hub gene) was associated with better survival in NSCLC. The immune infiltration analysis showed more CD4+ T cells in the resistant group with high expression of SPP1. SPP1 and CD44 promoters' methylations were independent prognostic factors of LUAD. And the expression level of SPP1 related to the sensitivity of EGFR-TKIs in multiple cancer cell lines. qRT-PCR validated the higher expression of SPP1 in EGFR-mutant LUAD than in normal tissue. Conclusion: Our study suggested that the upregulation of SPP1 might induce resistance to the 1st and 2nd generation EGFR-TKI, and influence tumor immune infiltration, resulting in poor survival. ZEB1, SPP1, MUC1, CD44, and ESRP1 might be molecular drivers of SCLC transformation of TKI resistance."

基金机构："Natural Science Foundation Project of Chongqing Science and Technology Commission (CSTC) , China [cstc2018jcyjAX0012]"

基金资助正文："This study was supported by the Natural Science Foundation Project of Chongqing Science and Technology Commission (CSTC) , China (grant no. cstc2018jcyjAX0012)."