Author of

• 18974

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  P3.02 - Biology/Pathology (ID 620)

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

  • 24007

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    P3.02-059 - T790M and C797S as Mechanisms of Acquired Resistance to Dacomitinib in Cell Models (ID 10314)

    09:30 - 09:30  |  Author(s): S. Ohara
    • Abstract

    Background:
    The ARCHER 1050 trial demonstrated the superiority of dacomitinib to gefitinib in terms of PFS. Lung cancers inevitably acquire resistance to these TKIs after an initial dramatic response. We previously reported that L792F and C797S, in addition to the major T790M, can develop in afatinib-resistant cells (Mol Cancer Ther 2017; 16: 357-64). This study aimed to clarify the mechanisms of acquired resistance to dacomitinib.
    
    Method:
    EGFR Del19, L858R, and G719A were introduced into Ba/F3 cells using retroviral vector. Dacomitinib-resistant clones were established from these Ba/F3 cells by exposure to fixed concentrations of dacomitinib (20nM or 200nM) using N-ethyl-N-nitrosurea (ENU) mutagenesis. EGFR secondary mutations were analyzed by Sanger sequence.
    
    Result:
    ENU mutagenesis screening established 21 dacomitinib-resistant clones so far: 10 Del19 clones with 20nM, 9 Del19 clones with 200nM, and 2 L858R clones with 20nM. T790M and each original mutation were detected in all of these resistant clones by mutational analyses.
    
    Conclusion:
    These preliminary data demonstrate that dacomitinib can directly induce T790M secondary mutation without selecting de novo T790M clones. Osimertinib could be potentially effective for a subset of lung cancers which acquired resistance to dacomitinib. Updated additional data will be presented.