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  P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)

  • Event: WCLC 2018
  • Type: Poster Viewing in the Exhibit Hall
  • Track:
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall

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    P1.01-05 - Metformin in Combination with Crizotinib for The Treatment of EML4-ALK+ Lung Cancer. (ID 12801)

    16:45 - 18:00  |  Presenting Author(s): Abigail Bland
    • Abstract
    • Slides

    Background
    

    Lung cancer accounts for the highest incidence of cancer mortality worldwide, equating to around 2 million deaths each year. Oncogenic receptor tyrosine kinases (RTK) have been discovered to play a role in cancer progression, and can be the target of novel therapeutics. The anaplastic lymphoma kinase receptor (ALK) is an RTK, and as a result of a chromosomal 2 rearrangement, fuses with echinoderm microtubule associated protein like-4 (EML4) forming the oncogenic EML4-ALK receptor. EML4-ALK contributes to 2-7% of all lung cancer cases and currently the first-line treatment is crizotinib, a tyrosine kinase inhibitor. Although crizotinib produces tumor regression, most patients will develop resistance, constituting a major research problem. Novel strategies are being explored and one such treatment is the anti-hyperglycemic, metformin. Epidemiological studies have shown that metformin reduces the risk of cancer and pre-clinical studies are examining this cytotoxic effect. This work aimed to determine the cytotoxicity and mechanism of a crizotinib/metformin combination in vitro in EML4-ALK+ lung cancer.

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    Crizotinib, metformin and the combination were examined using EML4-ALK+ human lung adenocarcinoma cells (H3122), ALK-/KRAF+ human lung adenocarcinoma cells (A549) and crizotinib-resistant (CR-H3122) cells maintained in crizotinib (0.8 µM). Cytotoxicity was tested using the sulforhodmaine B assay and to assess the validity of this assay the MTT assay was used as a comparison. Western blotting examined changes in ALK, p-ALK, mTOR, p-mTOR. Propidium iodine staining and flow cytometry examined changes in the cell cycle in H3122 cells.

    4c3880bb027f159e801041b1021e88e8 Result
    

    Crizotinib exhibits greater potency in H3122 cells compared to the ALK- A549 (IC₅₀’s of 0.16 µM vs. 1 µM). Interestingly, the addition of metformin (5 mM) to both cell lines did not change the IC₅₀, however, reduced cell viability by ~30% at lower doses of crizotinib. The MTT assay found the same effect. The IC₅₀ of metformin in H3122 cells was 22 mM, whereas this potency was lost in CR-H3122 cells (only a 50% reduction in cell viability with 50 mM). Mechanistically it was discovered that metformin decreases mTOR phosphorylation, a downstream protein of ALK, but has no effect on p-ALK. Both crizotinib and metformin produced a G1 phase arrest, with the effect being enhanced with the combination.

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    Metformin enhances the effect of low dose crizotinib. It appears that metformin acts by targeting the downstream protein, mTOR, and produces a G1 phase arrest, instead of directly inhibiting ALK. The addition of metformin to chemotherapeutics provides a potential treatment for EML4-ALK+ and other lung cancers.

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