Author of

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  P3.05 - Poster Session 3 - Preclinical Models of Therapeutics/Imaging (ID 159)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/30/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 12419

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    P3.05-001 - Metformin sensitizes EGFR-TKI-resistant human lung cancer cells in vitro and in vivo through inhibition of IL-6/STAT3 axis and EMT reversal (ID 335)

    09:30 - 09:30  |  Author(s): L. Li
    • Abstract

    Background
    Tyrosine kinase inhibitors (TKIs) that target the epidermal growth factor receptor (EGFR) has become standard therapy in patients with EGFR activating mutations. Unfortunately, acquired resistance eventually limits the clinical effects and application of EGFR-TKIs. Although main mechanisms of acquired resistance have been detected with varying frequencies, including T790M mutation, amplicfication of other kinases and epithelial to mesenchymal transition(EMT), potential therapies for these tumors have not been modeled in vivo. Researches have shown that suppression of EMT and IL-6/STAT3 pathway may abrogate this acquired mechanism of drug resistance of TKI.

    Methods
    By using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT), immunofluorescence, Western blot, cell tracking, invasion assay, ELISA assay and xenograft experiments, we analyzed the effect of metformin and TKIs on TKI resistance of tumor cells both in vitro and in vivo.

    Results
    Metformin, which is widely used as an antidiabetic agent, effectively increased sensitivy of TKI-resistant lung cancer cells to erlotinib or gefitinib. Metformin reversed EMT and decreased IL-6/STAT3 activation in TKI-resistant cells, while IL-6 addition in those cells bypassed the antitumor effect of metformin. Furthermore, overexpression or addition of IL-6 in TKI sensitive cells induced TKI resistance, which can be overcomed by metformin. Lastly, metformin-based combinatorial therapy effectively block tumor growth in xenografts involving TKI-resistant cancer cells, which is associated with EMT reversal and decreased IL-6/STAT3 activation.

    Conclusion
    Thus, the unexpected ability of metformin to reverse EMT and inactivate IL-6 axis further reveals that this biguanide, generally considered non-toxic and remarkably inexpensive, might be used in combination with TKIs in NSCLC patients harboring EGFR mutations to overcome TKI resistance. Our findings therefore offer preclinical proof of principle that combination of TKI and metformin may benefit patients with NSCLC.