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Guillaume Lessene



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    MA27 - Novel Drugs and PDX Models (ID 931)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 13:30 - 15:00, Room 206 BD
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      MA27.09 - Dual Inhibition of BCL-XL and MCL-1 is Required to Induce Tumour Regression in Lung Squamous Cell Carcinomas Sensitive to FGFR Inhibition (ID 12645)

      14:30 - 14:35  |  Author(s): Guillaume Lessene

      • Abstract
      • Presentation
      • Slides

      Background

      Fibroblast growth factor receptor 1 (FGFR1) gene amplification has been described in 20% of lung squamous cell carcinoma (SqCC), suggesting that FGFR tyrosine kinase inhibitors may constitute a new therapeutic approach for patients carrying this genetic alteration. However, a recently completed clinical trial reported low response rates to FGFR therapy, indicating the need for refined biomarkers. We have recently described that high levels of FGFR1 RNA expression better predicts response to FGFR inhibitors, yet the treatment results in tumour cell stasis as opposed to cell death. BH3-mimetics are a class of anticancer agents that block the BCL-2 family of pro-survival proteins to induce cell death and were recently approved for clinical use in blood cancers. We therefore hypothesized that combining BH3-mimetics with FGFR-targeted therapy may enhance the killing of SqCC cells.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We developed patient-derived xenograft models of lung squamous cell carcinoma and evaluated the activity of specific inhibitors of BCL-XL (A1331852), BCL-2 (ABT-199), MCL-1 (S63845) or FGFR (BGJ398) as single agents or in combination in vitro and in vivo. Genetic knockout of BCL-XL was also performed using CRISPR/Cas9. We evaluated compounds synergy in vitro using BLISS assay and in vivo efficacy using mRECIST.

      4c3880bb027f159e801041b1021e88e8 Result

      Here we demonstrate that FGFR therapy primes SqCC for cell death by increasing the expression of the pro-apoptotic protein BIM. We identified a greater reliance of lung SqCC cells on BCL-XL compared to BCL-2 for survival. However, neither BCL-XL nor MCL-1 inhibitor alone gives a survival benefit in combination FGFR therapy in vivo. In contrast, triple BCL-XL, MCL-1 and FGFR inhibition resulted in tumour volume regression and prolonged survival in vivo, demonstrating the ability of BCL-XL and MCL-1 proteins to compensate for each other in lung SqCC.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our work therefore provides a rationale for the simultaneous inhibition of MCL-1, BCL-XL and FGFR1 to maximize therapeutic response in FGFR1-expressing lung SqCC.

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