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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月26日

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  • Xiao Liang,
  • Jiali Xu,
  • Suhui Shu,
  • Wei Lv,
  • Dandan Yin,
  • Sunan Miao,
  • Xiyi Lu,
  • Chen Zhang,
  • Xinyin Liu,
  • Jiali Dai,
  • Jun Li,
  • Weibing Wu,
  • Erbao Zhang,
  • Renhua Guo

摘要

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.