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

  • 26599

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    P1.13-10 - Aurora Kinase A Drives the Evolution of Resistance to Third Generation EGFR Inhibitors in Lung Cancer (ID 13433)

    16:45 - 18:00  |  Author(s): Khyati Shah
    • Abstract

    Background
    

    Paradigm defining for precision medicine, EGFR inhibitors are a major breakthrough in the treatment of EGFR-mutant non-small cell lung cancer (NSCLC). Although these EGFR-TKI therapies often elicit profound initial therapeutic responses, their effects are transient due to residual disease. This residual disease and subsequent disease progression occurs through tumor evolution and molecular drivers behind the formation, maintenance and evolution of residual disease and acquired resistance have remained elusive. Although in many cases pre-existing clones with bona-fide genetic resistance have been identified, majority of patients have undetectable resistance causing genetic alterations suggesting that non-genetic alterations may drive altered cell state and signaling associated with EGFR inhibitor resistance. Furthermore, in the case of osimertinib now used in first line setting, mechanisms of acquired resistance have been ill defined and no effective second line therapies exist.

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    Using EGFR mutant lung cancer cells we developed eight distinct in vitro models of acquired resistance to 3rd generation EGFR-TKI inhibitors, osimertinib and rociletinib. We examined the efficacy of drug combinations in vivo using both cell line xenografts and PDX models of EGFR TKI resistance. We measured the level of staining of the candidate biomarker, TPX2, in patients progressing on first and third-generation EGFR TKIs.

    4c3880bb027f159e801041b1021e88e8 Result
    

    Chemical screens in acquired resistant cell lines revealed that Aurora kinase inhibitors are highly synergistic when combined with third-generation EGFR inhibitors. Resistant cells harbored heightened activation of AURKA caused by upregulation of its co-activator protein TPX2. In in-vitro and in-vivo models of acquired resistance the combination induced potent cell death by reactivating BIM-mediated apoptosis. We found that tumors from the majority of patients progressing on first and third-generation EGFR TKIs harbored high levels of TPX2, indicating that AURKA is likely activated and driving resistance in a significant fraction of EGFR-mutant lung cancers.

    Tracking the kinetics of AURKA activation, we found that AURKA activity is required for the formation and maintenance of residual drug tolerant cells, precursors of acquired resistance. Either single agent EGFR-TKI, the AURKA inhibitor MLN8237 or the combination enhanced the magnitude of response and forestalled the emergence of resistance in vitro as compared to monotherapies. The combination robustly induced tumor regressions in an EGFR L858R PDX tumor model generated from a residual disease surgical specimen.

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    This synthetic lethal interaction between EGFR TKIs and Aurora kinase inhibitors has important clinical implications for the development of better treatment strategies using EGFR-TKIs and suggest a new paradigm for preventing the emergence of resistance.

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