Unraveling EGFR-TKI resistance in lung cancer with high PD-L1 or TMB in EGFR-sensitive mutations
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 programm...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-01-01
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| Series: | Respiratory Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12931-023-02656-3 |
| _version_ | 1797349712935780352 |
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| author | Wuwu Ding Pengmin Yang Xiaokai Zhao Xiaozhi Wang Huaqing Liu Qing Su Xintao Wang Jieyi Li Ziying Gong Daoyun Zhang Xinwei Wang |
| author_facet | Wuwu Ding Pengmin Yang Xiaokai Zhao Xiaozhi Wang Huaqing Liu Qing Su Xintao Wang Jieyi Li Ziying Gong Daoyun Zhang Xinwei Wang |
| author_sort | Wuwu Ding |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T12:35:21Z |
| format | Article |
| id | doaj.art-58e08f7e504a4fe3a38c0535a3aae36f |
| institution | Directory Open Access Journal |
| issn | 1465-993X |
| language | English |
| last_indexed | 2024-03-08T12:35:21Z |
| publishDate | 2024-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Respiratory Research |
| spelling | doaj.art-58e08f7e504a4fe3a38c0535a3aae36f2024-01-21T12:31:30ZengBMCRespiratory Research1465-993X2024-01-0125111110.1186/s12931-023-02656-3Unraveling EGFR-TKI resistance in lung cancer with high PD-L1 or TMB in EGFR-sensitive mutationsWuwu Ding0Pengmin Yang1Xiaokai Zhao2Xiaozhi Wang3Huaqing Liu4Qing Su5Xintao Wang6Jieyi Li7Ziying Gong8Daoyun Zhang9Xinwei Wang10Department of Pathology, Deyang Pelple’s HospitalJiaxing Key Laboratory of Precision Medicine and Companion Diagnostics, Jiaxing Yunying Medical Inspection Co., LtdJiaxing Key Laboratory of Precision Medicine and Companion Diagnostics, Jiaxing Yunying Medical Inspection Co., LtdJiaxing Key Laboratory of Precision Medicine and Companion Diagnostics, Jiaxing Yunying Medical Inspection Co., LtdJiaxing Key Laboratory of Precision Medicine and Companion Diagnostics, Jiaxing Yunying Medical Inspection Co., LtdJiaxing Key Laboratory of Precision Medicine and Companion Diagnostics, Jiaxing Yunying Medical Inspection Co., LtdDepartment of R&D, Zhejiang Yunying Medical Technology Co., Ltd.Jiaxing Key Laboratory of Precision Medicine and Companion Diagnostics, Jiaxing Yunying Medical Inspection Co., LtdJiaxing Key Laboratory of Precision Medicine and Companion Diagnostics, Jiaxing Yunying Medical Inspection Co., LtdJiaxing Key Laboratory of Precision Medicine and Companion Diagnostics, Jiaxing Yunying Medical Inspection Co., LtdDepartment of Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & Affiliated Cancer Hospital of Nanjing Medical UniversityAbstract 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.https://doi.org/10.1186/s12931-023-02656-3EGFR-TKIsPD-L1TMBResistancePI3K signaling pathway |
| spellingShingle | Wuwu Ding Pengmin Yang Xiaokai Zhao Xiaozhi Wang Huaqing Liu Qing Su Xintao Wang Jieyi Li Ziying Gong Daoyun Zhang Xinwei Wang Unraveling EGFR-TKI resistance in lung cancer with high PD-L1 or TMB in EGFR-sensitive mutations Respiratory Research EGFR-TKIs PD-L1 TMB Resistance PI3K signaling pathway |
| title | Unraveling EGFR-TKI resistance in lung cancer with high PD-L1 or TMB in EGFR-sensitive mutations |
| title_full | Unraveling EGFR-TKI resistance in lung cancer with high PD-L1 or TMB in EGFR-sensitive mutations |
| title_fullStr | Unraveling EGFR-TKI resistance in lung cancer with high PD-L1 or TMB in EGFR-sensitive mutations |
| title_full_unstemmed | Unraveling EGFR-TKI resistance in lung cancer with high PD-L1 or TMB in EGFR-sensitive mutations |
| title_short | Unraveling EGFR-TKI resistance in lung cancer with high PD-L1 or TMB in EGFR-sensitive mutations |
| title_sort | unraveling egfr tki resistance in lung cancer with high pd l1 or tmb in egfr sensitive mutations |
| topic | EGFR-TKIs PD-L1 TMB Resistance PI3K signaling pathway |
| url | https://doi.org/10.1186/s12931-023-02656-3 |
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