D-mannose induces TFE3-dependent lysosomal degradation of EGFR and inhibits the progression of NSCLC.

In non-small cell lung cancer (NSCLC), the overexpression or abnormal activation of epidermal growth factor receptor (EGFR) is associated with tumor progression and drug resistance. EGFR tyrosine kinase inhibitors (TKIs) are currently the first-line treatment of NSCLC. However, patients inevitably acquired EGFR TKIs resistance mutations, which led to disease progression, so it is urgent to find new treatment. Here, we report that D-mannose up-regulates lysosomal activity by enhancing TFE3-mediated lysosomal biogenesis, thereby increasing the degradation of EGFR and significantly down-regulating its protein level. Therefore, D-mannose significantly inhibited the proliferation, migration and invasion of wild-type EGFR (WT-EGFR) and EGFR mutant cells (E746-A750 deletion, L858R and T790M mutations) in vitro. Oral administration of D-mannose strongly inhibited tumor growth in mice, showing similar effects with osimertinib. Taken together, these data suggest that D-mannose may represent a new strategy for clinical treatment of NSCLC.