Author of

• 20182

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  P3.03 - Chemotherapy/Targeted Therapy (ID 719)

  • Event: WCLC 2017
  • Type: Poster Session with Presenters Present
  • Track: Chemotherapy/Targeted Therapy
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)

  • 24055

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    P3.03-010 - Identification of Mechanisms of Drug Resistance in RET-Rearranged Lung Cancer (ID 8637)

    09:30 - 09:30  |  Presenting Author(s): Takashi Nakaoku
    • Abstract
    • Slides

    Background:
    Oncogenic fusions of the RET kinase gene, which was discovered by us in 1‒2% of LADCs (Kohno et al, Nat Med, 2012), have been suggested as a therapeutic target for existing tyrosine kinase inhibitors (TKIs). Actually, several clinical trials investigating RET tyrosine kinase inhibitors (TKIs) for the therapy of RET-positive LAD showed promising clinical outcome. However, the cancer inevitably acquires resistance to TKI like other driver oncogene positive LAD.
    
    Method:
    To identify a mechanism of TKI resistance in RET-driven lung cancer, we generated resistant cells to several RET-TKIs using LC-2/Ad cells that are RET-rearranged lung cancer cell lines. In addition, we established cells stably expressing RET fusion cDNA and RET-rearranged cells edited by CRISPR/Cas9, and generated resistant cells using these cells. We performed targeted sequencing covering 50 genes on a pair of resistant and pre-treatment cells. To identify the bypath track, then we performed antibody array and investigated change of mRNA expressions.
    
    Result:
    No genetic alteration was found in resistant cells by targeted sequencing. Antibody array found the activation of other tyrosine kinase, including EGFR and other HER family. Actually, the addition of the growth factors activating the kinases reduced the inhibitory effect of the TKIs. In addition, the TKI to suppress signaling of the kinase in combination with RET TKI reduced the cell viability in resistant cells.
    
    Conclusion:
    The inhibition of bypath track in combination of RET signaling could be an effective therapy for RET-rearranged lung cancer. In the meeting we plan to report the progress.
    
    

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