Author of

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  P2.01 - Advanced NSCLC (Not CME Accredited Session) (ID 950)

  • Event: WCLC 2018
  • Type: Poster Viewing in the Exhibit Hall
  • Track:
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall

  • 26893

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    P2.01-89 - Synergistic Cytotoxicity Through MAPK/ERK Pathway and ALK Inhibition in Crizotinib Resistant EML4-ALK-Positive Lung Cancer (ID 11310)

    16:45 - 18:00  |  Presenting Author(s): Nensi Shrestha
    • Abstract
    • Slides

    Background
    

    Anaplastic lymphoma kinase (ALK)-positive lung cancer is an aggressive cancer that most commonly arises through EML4-ALK chromosomal fusion. Crizotinib is the first-line treatment for ALK-positive lung cancer, providing a greater progression free survival and overall response rate than chemotherapy. However, patients invariably develop acquired resistance, usually within a year. Mechanisms of resistance include copy number gain, secondary mutations in ALK, or activation of bypass signalling pathways. The aim of this study was to investigate the combination effect of ALK inhibitor, crizotinib, and MEK inhibitor, selumetinib, in crizotinib resistance ALK-positive lung cancer cells.
    

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    Cytotoxicity of single and combined treatment of crizotinib and selumetinib in ALK-positive (H3122), ALK-negative (A549) and crizotinib resistance ALK-positive (CR-H3122) cells was determined by Sulforhodamine B assay. Chou-Talay analysis was performed to determine the nature of interaction between the two drugs used in combination treatment. Endogenous expression of p-ALK and p-ERK was determined by western blotting. The effect of combination treatment on cell cycle arrest and apoptosis induction was determined by flow cytometer.
    

    4c3880bb027f159e801041b1021e88e8 Result
    

    Combined treatment with crizotinib and selumetinib had significantly greater cytotoxicity and showed a synergistic effect compared to the single drug treatments in H3122 cells. The combination treatment had no synergistic effect in A549 cells, indicating that the cytotoxic effect was specific to ALK. The most prominent cytotoxic effect of the combination treatment was observed with CR-H3122 cells, with synergistic suppression of cell viability even at low drug concentrations. Endogenous protein expression of p-ALK and p-ERK was decreased by combination of crizotinib and selumetinib. Moreover, combination treatment lead to increased G1 arrest and apoptosis compared to single treatment in H3122 cells.
    

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    Our results showed that combination of crizotinib and selumetinib have potent cytotoxic effects in crizotinib resistant ALK-positive lung cancer. The proposed combination treatment could be a promising therapy for acquired crizotinib resistant ALK-positive lung cancers.
    

    6f8b794f3246b0c1e1780bb4d4d5dc53

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