Author of

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  P2.14 - Targeted Therapy (ID 183)

  • Event: WCLC 2019
  • Type: Poster Viewing in the Exhibit Hall
  • Track: Targeted Therapy
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall

  • 31555

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    P2.14-35 - 2-Deoxy-D-Glucose Sensitizes Non-Small Cell Lung Cancer with EML4-ALK Fusion to Crizotinib via Suppression of HK2 Through AKT/mTOR Passway   (ID 749)

    10:15 - 18:15  |  Author(s): Yuanyuan Song
    • Abstract
    • Slides

    Background
    

    ALK-positive NSCLC cells (ALK⁺ NSCLC) present high glycolysis. Targeting cancer cell metabolism with the glycolysis inhibitor, 2-deoxyglucose (2DG), is a viable strategy that sensitizes the fist-line ALK-TKI crizotinib; but the effects of combination of 2DG and Crizotinib on ALK⁺ NSCLC cells and the mechanism of action are unknown.

    Method
    

    ALK⁺ NSCLC cells H2228 and H3122 were incubated with crizotinib with or without 2DG, and subjected to the MTT. H2228 cells was treated with crizotinib or/and 2DG to explore the impact of cell growth and potential mechanism of action by clones formation, Ki67 incorporation assay, small interfering RNA technology, Western blot analysis.

    Result
    

    A clear synergistic anti-proliferative interaction between 2DG and crioztinib was observed with a combination index value<1 (CI<1).The combination of crizotinib and 2DG effectively inhibited the clones formation and invasion ability of H2228 cells. The glucose consumption and Lactate production of H2228 cell treated with increasing concentration of 2DG was reduced to accompany a markedly decrease of HK2 expression. ALK-positive NSCLC cells showed a higher level expression of HK2 than ALK-negative NSCLC, down-regulation of HK2 by siRNA, obviously enhanced the ability of crizotinib to suppress proliferation activity. The westblot results displayed a significantly inhibition of AKT/mTOR signaling pathway in H2228 cells treatment with combination of 2DG and crizotinib.

    Conclusion
    

    This study demonstrated that 2DG would be a promising drugs to sensitize crizotinib via suppressing HK2 expression to inhibit the activity of AKT/mTOR signaling pathway induced by ALK phosphorylation.

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