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  P3.01 - Advanced NSCLC (Not CME Accredited Session) (ID 967)

  • Event: WCLC 2018
  • Type: Poster Viewing in the Exhibit Hall
  • Track:
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall

  • 27380

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    P3.01-27 - Characterization and Sensitization of Non-Small Cell Lung Cancer Cell Line Variants Selected for Resistance to Osimertinib (ID 12145)

    12:00 - 13:30  |  Author(s): James Koropatnick
    • Abstract
    • Slides

    Background
    

    Many non-small cell lung cancers (NSCLC) are oncogenically driven by mutant epidermal growth factor receptor (EGFR). EGFR tyrosine kinase inhibitors (TKIs) are commonly used as first-line treatments against such tumours, but NSCLC tumours recur with novel EGFR mutation(s) (often a T790M mutation in exon 20) that confers resistance to these drugs [Ther Adv Respir Dis 10(6): 549-565, 2016]. Third generation EGFR TKIs (e.g., osimertinib) have been designed that are highly active against both T790M EGFR and the original oncogenic EGFR lacking the T790M mutation. Clinical resistance to third generation TKIs has been observed, but model systems in which to study the mechanisms of resistance are few. The human NSCLC cell line H1650 has the EGFR-activating mutation del E746-A750. The human NSCLC line H1975, derived from an EGFR-TKI-resistant tumor, contains EGFR-activating mutation L858R as well as resistance-conferring T790M. To explore mechanisms mediating resistance to third generation TKIs, we selected variants of the H1650 and H1975 cell lines for resistance to osimertinib to create models in which mechanisms of resistance can be characterized and tested for potential methods to overcome that resistance.

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    Cells were exposed continuously to a single concentration of osimertinib, in some cases with the inclusion of verapamil to avoid possible selection of multidrug-resistant cells. After 4 weeks, with weekly changes of drug-medium, clonal cell lines were selected from H1650 cultured in the presence of 25 or 50 µM osimertinib plus 10 µM verapamil, and selected from H1975 cultured in 6 or 10 µM osimertinib alone or 5 µM osimertinib plus 10 µM verapamil.

    4c3880bb027f159e801041b1021e88e8 Result
    

    The H1650 osimertinib-resistant cell lines (H1650/osi-25a/VPL and H1650/osi-50a/VPL) are 1.6- to 1.8-fold resistant to osimertinib. The H1975 osimertinib-resistant cell lines (H1975/osi-6b, osi-10c, and osi-5b/VPL) were, respectively, 90-, 95-, and 38-fold resistant to osimertinib. None of the cell lines was cross-resistant to imatinib. The compound 2-(benzylsulfonyl)-1-(1H-indol-3-yl)-1,2-dihydroisoquinoline (IBR2) is an inhibitor of the DNA repair protein RAD51 and enhances cytotoxicity of EGFR inhibitors against numerous cell lines (Ferguson et al., JPET 2018, doi.org/10.1124/jpet.117.241661). IBR2 decreased osimertinib-resistance by up to 80% in the H1650- and H1975-derived osimertinib-resistant cell lines. Further analyses of the resistant cell lines are being undertaken.

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    The H1650 and H1975 osimertinib-resistant cell lines are a valuable resource in which to test methods to circumvent resistance to third generation EGFR TKIs.

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