Author of

• 25933

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  P1.13 - Targeted Therapy (Not CME Accredited Session) (ID 945)

  • Event: WCLC 2018
  • Type: Poster Viewing in the Exhibit Hall
  • Track:
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall

  • 26595

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    P1.13-07 - Epithelial-Mesenchymal Transition Induced the Acquired Resistance to ALK Inhibitor Brigatinib in Lung Cancer Cells Harboring with ALK Fusions (ID 12675)

    16:45 - 18:00  |  Author(s): Junji Uchino
    • Abstract

    Background
    

    The ALK inhibitors, such as crizotinib and alectinib show a great response to patients with non-small cell lung cancer (NSCLC) harboring ALK fusions. However, the acquired drug resistance is also known as important issues in the treatment with the specific molecular targeted agents, such as EGFR-TKI as well as ALK-TKI. The mechanisms of acquired resistance to ALK-TKI are reported previously, bypass tract signals of EGFR or MET, and Epithelial-mesenchymal transition (EMT). Novel generation ALK inhibitor brigatinib is promising for NSCLC harboring ALK fusions, however, the precise mechanism of the acquired resistance to brigatinib is not fully understood. To elucidate for the novel acquired resistance to brigatinib, we here conducted the cell-based experiments using ALK fusion NSCLC cells.

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    We established ALK fusion NSCLC cells H3122 (variant 1 E13;A20) and H2228 (variant 3 E6; A20) with the acquired resistance to brigatinib by step-wise methods. ALK inhibitor sensitivity and signal transduction in H3122 and H2228 cells were examined in vitro.

    4c3880bb027f159e801041b1021e88e8 Result
    

    H3122-brigatinib resistance cell (H3122-BR) and H2228-brigatinib resistance cell (H2228-BR) indicated the cross-resistance to other ALK inhibitors alectinib, crizotinib and lorlatinib. Furthermore, morphological change was observed to spindle shape, and additionally shows decreasing of E-cadherin and increasing of vimentin which are marker of EMT by the western blotting analysis. Moreover, some of these resistant cells cultured with drug-free medium for 4weeks were reversed the sensitivity to ALK-TKIs and cell formation backed to parental cells.

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    We demonstrated that EMT elicited the acquired resistance to ALK-TKIs under the exposure of brigatinib treatment in ALK fusion NSCLC cells. Further experiments are needed to overcome this drug resistance induced by EMT.

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