2. Academic Validation
  3. GLMP promotes EGFR-TKI resistance by activating autophagy and RhoA pathway in non-small cell lung cancer

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

  • NPJ Precis Oncol. 2025 Nov 26;9(1):391. doi: 10.1038/s41698-025-01135-w.
Xiao Liang # 1 2,  Jiali Xu # 1,  Suhui Shu # 3,  Wei Lv # 3,  Dandan Yin # 4,  Sunan Miao 3,  Xiyi Lu 1,  Chen Zhang 1,  Xinyin Liu 1,  Jiali Dai 1,  Jun Li 1,  Weibing Wu 5,  Erbao Zhang 6 7,  Renhua Guo 8
Affiliations

Affiliations

  • 1 Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
  • 2 Department of Oncology, the Affiliated Jiangyin Hospital of Nantong University, Wuxi, China.
  • 3 Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.
  • 4 Clinical Research Center, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, China.
  • 5 Department of Thoracic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. [email protected].
  • 6 Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China. [email protected].
  • 7 Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China. [email protected].
  • 8 Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. [email protected].
  • # Contributed equally.
PMID: 41298761 DOI: 10.1038/s41698-025-01135-w
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.

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