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E. Tsakiridis



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    Poster Display session (Friday) (ID 65)

    • Event: ELCC 2018
    • Type: Poster Display session
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 4/13/2018, 12:30 - 13:00, Hall 1
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      69P - The diabetes drug canagliflozin sensitizes non-small cell lung cancer (NSCLC) to radiotherapy and chemotherapy (ID 494)

      12:30 - 13:00  |  Author(s): E. Tsakiridis

      • Abstract

      Background:
      Radiotherapy (RT) and chemotherapy (ChT) are key treatments for NSCLC, but this disease is highly resistant to cytotoxic therapy. Metabolism determines tumor cell survival and response to therapy. Oncogenic pathways like EGFR- > K-Ras- > mTOR stimulate glycolysis, protein and lipid synthesis (lipogenesis). This is balanced by the action of metabolic stress sensors like AMP-activated kinase (AMPK), which is activated by stressors, including inhibition of mitochondrial oxidative phosphorylation (OxPhos) cascade. AMPK mediates energy conservation through a global regulation on metabolism that includes suppression of lipogenesis, protein synthesis and mTOR. Canagliflozin is an approved and effective diabetes drug that blocks the Na-glucose co-transporter 2 (SGLT2), which controls glycemia by blocking glucose re-uptake in the kidney. However, we found that canagliflozin also inhibits mitochondria OxPhos Complex I and activates AMPK, leading to blockade of lipogenesis and a significant anti-tumor activity in NSCLC.

      Methods:
      Adenocarcinoma A549 and H1299 NSCLC cells were subjected to canagliflozin, RT and cisplatin ChT treatments and were analyzed with proliferation, clonogenic survival and immunoblotting experiments.

      Results:
      We report that canagliflozin enhances the response of NSCLC cells to RT and ChT. Canagliflozin, but not other clinically used SGLT2 inhibitors, like Empagliflozin or Dapagliflozin, suppresses proliferation and clonogenic survival of A549 and H1299 cells and enhances their response to RT and cisplatin ChT. Importantly, canagliflozin mediates these effects at clinically achievable low micromolar doses (5–30 mM). These effects are associated with potent inhibition of OxPhos complex I, phosphorylation and activation of AMPK, inhibitory phosphorylation of Acetyl-CoA carboxylase (ACC) and suppression of the mTOR pathway.

      Conclusions:
      This work suggests that canagliflozin is a promising metabolism-targeting therapy that may be able to improve clinical RT/ChT responses in NSCLC. Being, a well-tolerated, approved and widely used medication, canagliflozin may be able to enter early phase NSCLC trials in the near future.

      Clinical trial identification:


      Legal entity responsible for the study:
      McMaster University

      Funding:
      Has not received any funding

      Disclosure:
      All authors have declared no conflicts of interest.