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  P1.03 - Biology (Not CME Accredited Session) (ID 935)

  • 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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    P1.03-20 - The Novel SFN Inhibitors Aprepitant and Ticagrelor Exert Anti-Tumor Effects Through Blocking of Oncoprotein Ubiquitination (ID 12110)

    16:45 - 18:00  |  Author(s): Takatsugu Hirokawa
    • Abstract
    • Slides

    Background
    

    We have previously shown that the gene encoding stratifin (SFN, 14-3-3 sigma) is differentially expressed during the course of progression from AIS to early invasive adenocarcinoma (eIA), inducing early tumor progression by binding to SKP1 and blocking the activity of SCF^FBW7 ubiquitin ligase. As suppression of SFN significantly reduces cell growth and tumor formation or progression, we expected that inhibition of SFN could be a promising therapeutic strategy for lung adenocarcinoma.

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    To identify candidate compounds that bind specifically to SFN and block SFN-SKP1 binding, we carried out in silico library screening based on putative druggable sites of SFN around the SKP1 interaction interface using molecular docking against 7,133 bioactive compounds from the DrugBank database. Experimental validation was performed for 46 compounds that showed the highest docking scores. Cell growth and dissociation of SFN-SKP1 were examined by WST-8 assay and IP/western blotting after treatment with each compound. Finally, 4 candidate compounds were subjected to in vivo evaluation. Tumor-bearing mice that had received subcutaneous injection of A549 cells were subjected to two experimental schedules: 1) Daily oral administration of each compound starting at 1 day after injection until 21 days. 2) Same as 1) but starting when the tumors had reached 100 mm³ in size.

    4c3880bb027f159e801041b1021e88e8 Result
    

    Through in silico screening and experimental validation, we identified 4 compounds as SFN inhibitors: Aprepitant, Ticagrelor, Ezetimibe, and Chlorhexidine. All of them significantly and dose dependently reduced cell growth and SFN-SKP1 binding. Notably, Aprepitant completely blocked in vivo tumor formation, and Ticagrelor markedly reduced tumor progression when administered from the day after tumor cell injection. Furthermore, Aprepitant and Ticagrelor reduced tumor progression in a dose-dependent manner even when administration was started after tumors had grown to 100 mm³.

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    Here we have shown that inhibition of SFN-SKP1 binding results in an anti-tumor effect. Since SFN binding to SKP1 results in SCF^FBW7 dysfunction and allows oncoproteins such as cyclin E1 and c-Jun to evade ubiquitination and subsequent degradation, it is considered that inhibition of SFN will lead to ubiquitination of these oncoproteins. Although Aprepitant is a NK-1R (neurokinin-1 receptor) antagonist which is already approved as an antiemetic drug, and Ticagrelor is a reversible P2Y12 inhibitor exerting an anti-platelet effect, our results suggest that these agents could be applicable for treatment of lung adenocarcinoma.

    As overexpression of SFN starts from eIA, we believe that SFN inhibitors will provide a novel chemotherapeutic strategy for early-stage lung adenocarcinoma.

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