Enhanced Glycolysis Supports Cell Survival in EGFR-Mutant Lung Adenocarcinoma by Inhibiting Autophagy-Mediated EGFR Degradation

Oncogenic EGFR is essential for the development and growth of non-small cell lung cancer (NSCLC), but the precise roles of EGFR in lung cancer metabolism remain unclear. Here, we show that EGFR mutation-mediated enhancement of glycolysis is critical for EGFR stability. EGFR knockdown significantly decreased levels of glycolytic pathway intermediates via transcriptional regulation of glycolytic genes. EGFR mutation-enhanced glycolysis was required for fueling the tricarboxylic acid cycle, a critical component of EGFR stability. Nonsustained ATP production enhanced reactive oxygen species accumulation and subsequent JNK-mediated activation of autophagy, which in turn induced EGFR degradation. Our data show that EGFR-mutant NSCLCs require EGFR mutation-enhanced glycolysis to maintain EGFR stability. This pathway may serve as an attractive therapeutic target for EGFR-mutant NSCLCs. Enhanced glycolysis by EGFR mutation is required for maintaining EGFR levels via inhibition of JNK-induced autophagy. This provides a promising rationale for use of JNK activators in patients with EGFR-mutated NSCLC. .