GLUT1 sensitizes tumor cells to EGFR-TKIs by binding with activated EGFR and regulating its downstream signaling pathways.

BACKGROUND: We have previously demonstrated that GLUT1 can interact with phosphorylated EGFR and has an oncogenic role in lung cancer. Here, we aim to investigate their binding region and its signaling pathways. METHODS: The AlphaFold 3 prediction, Co-immunoprecipitation, and Western blot were used to uncover the interaction conditions of GLUT1 and EGFR. The RNA-seq data was analyzed to evaluate the difference in signaling pathways between wild-type EGFR and activated mutated EGFR. The xenograft tumor model was established to determine the therapy effect of the combination of GLUT1 inhibitor BAY-876 and EGFR TKI Osimertinib. RESULTS: We found that the interaction ability of GLUT1 and EGFR depended on the activation of EGFR. GLUT1 interacted with EGFRvIII (loss 2-7 exons) but not with EGFRvI (loss 1-16 exons), so GLUT1 interacts with EGFR in the EGFR extracellular transmembrane region. GLUT1 regulated EGFR downstream signaling pathways. GLUT1 inhibitor BAY-876 can sensitize tumor cells to EGFR TKI Osimertinib. CONCLUSIONS: GLUT1 participates in tumor progression by interacting with phosphor-EGFR, suggesting that inhibition of the GLUT1-EGFR axis may be a potential therapeutic strategy for lung cancer treatment.