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- Title
Unraveling EGFR-TKI resistance in lung cancer with high PD-L1 or TMB in EGFR-sensitive mutations.
- Authors
Ding, Wuwu; Yang, Pengmin; Zhao, Xiaokai; Wang, Xiaozhi; Liu, Huaqing; Su, Qing; Wang, Xintao; Li, Jieyi; Gong, Ziying; Zhang, Daoyun; Wang, Xinwei
- Abstract
Background: Although EGFR-TKI resistance mechanisms in non-small cell lung cancer (NSCLC) have been extensively studied, certain patient subgroups remain with unclear mechanisms. This retrospective study analysed mutation data of NSCLC patients with EGFR-sensitive mutations and high programmed death-ligand 1 (PD-L1) expression or high TMB to identify primary resistance mechanisms. Methods: Hybrid capture-based next-generation sequencing (NGS) was used to analyse mutations in 639 genes in tumor tissues and blood samples from 339 NSCLC patients. PD-L1 immunohistochemical staining was also performed on the same cell blocks. Molecular and pathway profiles were compared among patient subgroups. Results: TMB was significantly higher in lung cancer patients with EGFR-sensitive mutations and high PD-L1 expression. Compared with the high-expression PD-L1 or high TMB and low-expression or TMB groups, the top 10 genes exhibited differences in both gene types and mutation rates. Pathway analysis revealed a significant mutations of the PI3K signaling pathway in the EGFR-sensitive mutation group with high PD-L1 expression (38% versus 12%, p < 0.001) and high TMB group (31% versus 13%, p < 0.05). Notably, PIK3CA and PTEN mutations emerged as the most important differentially mutated genes within the PI3K signaling pathway. Conclusions: Our findings reveal that the presence of PI3K signaling pathway mutations may be responsible for inducing primary resistance to EGFR-TKIs in NSCLC patients with EGFR-sensitive mutations along with high PD-L1 expression or high TMB. This finding is of great significance in guiding subsequent precision treatments in NSCLC.
- Subjects
PROGRAMMED cell death 1 receptors; PROGRAMMED death-ligand 1; LUNG cancer; NON-small-cell lung carcinoma; IMMUNOSTAINING; KINASE inhibitors
- Publication
Respiratory Research, 2024, Vol 25, Issue 1, p1
- ISSN
1465-9921
- Publication type
Article
- DOI
10.1186/s12931-023-02656-3