Abnormal activation of epidermal growth factor receptor (EGFR) promotes the development of Non-Small Cell Lung Cancer Cells (NSCLC). Chemoresistance to tyrosine kinase inhibitors (TKIs), which is elicited by EGFR mutations, is a key challenge for NSCLC treatment. In the present study, we demonstrate a critical role of gasdermin E (GSDME), an important protein for pyroptosis, in the maintenance of EGFR stability and activation. We found that GSDME depletion suppressed the EGFR-mediated proliferation of NSCLC cells in vitro. GSDME knockdown downregulated the protein level of CCND1 and inhibited the phosphorylation of ERK1/2 in NSCLC cells. Mechanistically, both GSDME-FL and GSDME-N fragment physically interacted with EGFR. GSDME interacted with cytoplasmic fragment (CT) of EGFR. GSDME knockdown inhibited EGFR dimerization and phosphorylation at tyrosine 1173 (EGFR^Y1173), which could activate ERK1/2. GSDME knockdown promoted EGFR degradation and phosphorylation at tyrosine 1045 (EGFR^Y1045). Importantly, GSDME-FL increased the stability of EGFR, while the GSDME-N fragment induced EGFR degradation. Together, our results demonstrate that the GSDME-EGFR interaction plays an important role in NSCLC development, reveal a previously unrecognized link between GSDME and EGFR stability and offer new insight into cancer pathogenesis.

GSDME, EGFR, ERK1/2, Proliferation