Author of

• 18974

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  P3.02 - Biology/Pathology (ID 620)

  • Event: WCLC 2017
  • Type: Poster Session with Presenters Present
  • Track: Biology/Pathology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)

  • 24036

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    P3.02-088 - Enhanced Glycolysis Is Critical for Maintaining Inactivation of JNK and Stability of EGFR Leading to the Survival of EGFR-Mutant Lung Cancer Cells (ID 8134)

    09:30 - 09:30  |  Author(s): J.K. Rho
    • Abstract

    Background:
    Metabolic reprogramming is required for cancer cells to meet the demands of enhanced cell proliferation. In this study, we investigated how altered cell metabolism is associated with oncogenic mutant EGFR in lung cancer.
    
    Method:
    Metabolomics and measurement of metabolites in glycolytic pathway and TCA cycle were done using lung cancer cells with mutant EGFR and wild-type EGFR.
    
    Result:
    EGFR-mutant lung cancer cells showed enhanced glycolysis with elevated glucose uptake and lactate production which resulted in high extracellular acidification rate compared to cancer cells with wild-type EGFR. EGFR-TKI treatment or knockdown of EGFR caused a significant decrease in the metabolites of glycolysis. They are much more sensitive to glucose deprivation, but not to glutamine deprivation. Glutamine is usually utilized to fuel the TCA cycle supporting tumor cell growth. However, glucose was the main source of TCA cycle to produce ATP in EGFR-mutant cells. This mutant EGFR-enhanced glycolysis was critical for EGFR stability. The failure to sustain ATP production in mitochondria by glucose deprivation or suppression of glycolysis induced ROS accumulation which resulted in JNK activation. Activated JNK mediated EGFR degradation causing apoptosis while SP600125, a JNK inhibitor, could rescue cells from apoptotic cell death. Importantly, almost same effects could be observed in EGFR-TKI-resistant cells by T790M.
    
    Conclusion:
    Together, our data showed that EGFR-mutant lung cancer cells require the enhanced glycolysis for maintaining inactivation of JNK and EGFR stability regardless of T790M. This could be an attractive target for treatment of EGFR-mutant lung cancer, especially with resistance to EGFR-TKI.