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.