GLMP promotes EGFR-TKI resistance by activating autophagy and RhoA pathway in non-small cell lung cancer

Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) restricts the long-term efficacy of treatment in patients with lung cancer. Here, we report that the EGFR-TKI resistance mechanism is mediated by lysosome-related regulation. The overexpression of glycosylated lysosomal membrane protein (GLMP), a lysosomal membrane protein, promotes resistance to Osimertinib both in vitro and in vivo. Mechanistically, GLMP could regulate the ubiquitination of RhoA and promote resistance by activating the epithelial-mesenchymal transition (EMT), which involves the RhoA pathway and activates the late stage of autophagy. Inhibition of the RhoA pathway alone enhances the initiation stage of autophagy. Lysosomal hyperactivity in TKI-resistant cells sustains the flow of autophagy. Therefore, the combined inhibition of the RhoA pathway and autophagy can effectively attenuate EGFR-TKI resistance. Our findings provide a potential therapeutic strategy to overcome resistance to EGFR-TKIs.

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Publication Details

Journal
npj Precision Oncology
Published
2025-11-26
DOI
https://doi.org/10.1038/s41698-025-01135-w
Citations
2
Primary Topic
Autophagy in Disease and Therapy
Type
article
Field-Weighted Citation Impact
2.71

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article

GLMP promotes EGFR-TKI resistance by activating autophagy and RhoA pathway in non-small cell lung cancer

Xiaowen Liang, Renhua Guo, Xinyin Liu, Shuying Miao et al.
2 citations
npj Precision Oncology
Autophagy in Disease and Therapy
2.71
article

GLMP promotes EGFR-TKI resistance by activating autophagy and RhoA pathway in non-small cell lung cancer

Xiaowen Liang, Renhua Guo, Xinyin Liu, Shuying Miao, Wei Lv, Xiyi Lu, Erbao Zhang, Dandan Yin, Jiali Xu, Songren Shu, Weibing Wu, Jun Li, Chen Zhang, Jiali Dai
article en
2 citations

Abstract

Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) restricts the long-term efficacy of treatment in patients with lung cancer. Here, we report that the EGFR-TKI resistance mechanism is mediated by lysosome-related regulation. The overexpression of glycosylated lysosomal membrane protein (GLMP), a lysosomal membrane protein, promotes resistance to Osimertinib both in vitro and in vivo. Mechanistically, GLMP could regulate the ubiquitination of RhoA and promote resistance by activating the epithelial-mesenchymal transition (EMT), which involves the RhoA pathway and activates the late stage of autophagy. Inhibition of the RhoA pathway alone enhances the initiation stage of autophagy. Lysosomal hyperactivity in TKI-resistant cells sustains the flow of autophagy. Therefore, the combined inhibition of the RhoA pathway and autophagy can effectively attenuate EGFR-TKI resistance. Our findings provide a potential therapeutic strategy to overcome resistance to EGFR-TKIs.

npj Precision OncologyVol. 9(1)
Nanjing University of Chinese Medicine (CN), Nantong University (CN), Affiliated Hospital of Nantong University (CN), Jiangsu Cancer Hospital (CN), Jiangsu Province Hospital (CN), Nanjing Medical University (CN)
National Natural Science Foundation of China, Government of Jiangsu Province, Natural Science Foundation of Jiangsu Province, Xuzhou Medical University, Cancer Foundation of China
Openalex Percentile: Top 8%
Autophagy in Disease and Therapy
2.71
DOIOpen Access PDFOpenAlex
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