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V.C. Broaddus



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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
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      P3.05-019 - Bim expression in EGFR-mutant lung cancer 3D spheroids predicts responsiveness to tyrosine kinase inhibitors (ID 3173)

      09:30 - 09:30  |  Author(s): V.C. Broaddus

      • Abstract

      Background
      The pro-apoptosic Bcl-2 family member BIM is known to be a critical mediator of targeted therapy-induced apoptosis in lung cancer. Also, pretreatment level of BIM strongly predicted the capacity of EGFR inhibitors to induced apoptosis in EGFR-mutant cancers. But prevous studies were mostly done in two-dimensional (2D) cell cultures (monolayers).

      Methods
      So we used three-dimensional(3D) spheroid culture model that were proved to be a valuable platform to study acquired multicellular apoptotic resistance and effectively recapitulate some of the complexity of solid tumors such as mesothelioma. 3D spheroids with EGFR-mutant cell lines (H3255, HCC827, H1650, 11-18, H4006) were generated in polyHEMA-coated plates and TKI treatments were done both in 2D and 3D. The degree of apoptosis and expressions of BIM by immunoblotting before and after treatment were compared.

      Results
      Contrary to other solid tumors, spheroids showed more prominent apoptosis to TKI than monolayer. Spheroids expressed more BIM than did monolayers except H4006. BIM was not expressed in H4006 (2D, 3D), but BIM expression was found to be elevated after TKI treatment only in spheroids. Higher level of BIM in spheroids had the tendency of higher apoptotic response to TKI.

      Conclusion
      3D spheroids cultures are useful in studying apoptotic mechanism in EGFR-mutant lung cancer. BIM expression before and after treatment of TKI might be useful predictor in EGFR-mutant spheroids model. So therapies that upregulated BIM expression can improve the efficacy of TKI therapy.