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Douglas Graham



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    P1 - Poster Viewing (ID 5)

    • Event: NACLC 2019
    • Type: Poster Session
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 10/11/2019, 16:45 - 18:00, Exhibit Hall
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      P1.18 - MERTK Activation Drives Osimertinib Resistance in EGFR-mutated Non-small Cell Lung Cancer (ID 91)

      16:45 - 18:00  |  Author(s): Douglas Graham

      • Abstract

      Background:
      Non-small cell lung cancer (NSCLC) remains a global problem causing more deaths in both men and women than any other cancer worldwide with an urgent need for more efficacious treatments. During the last decade the therapeutic landscape for NSCLC has been profoundly changed with the discovery of activating mutations in Epidermal Growth Factor Receptor (EGFR) (EGFRMT). Osimertinib, a 3rd generation EGFR TKI, was recently FDA-approved as a front-line agent for newly diagnosed EGFRMT NSCLCs due to its superior efficacy relative to earlier-generation EGFR TKIs. However, unmet clinical needs have arisen in conjunction with osimertinib use, including understanding mechanisms of osimertinib resistance and developing novel approaches to prevent or reverse resistance and/or enhance osimertinib efficacy in responsive patients. Our group previously identified MERTK receptor tyrosine kinase as a potential therapeutic target in NSCLC and developed MRX-2843, a novel small molecule kinase inhibitor with dual MERTK and FLT3 activity, which is currently in Phase I clinical trials.


      Method:
      Induction of osimertinib resistance was achieved by culturing EGFRMT NSCLC cells in escalating doses of osimertinib and expression of MERTK was compared in parental and osimertinib-resistant derivative cell lines by immmunoblot. The role of MERTK and its ligands, GAS6 and PROS1, in osimertinib resistance was evaluated using cell expansion assays, immunoblot, clonogenic assays, and xenograft models.


      Results:
      Osimertinib resistance was confirmed in derivative cell lines by cell expansion and downstream signaling assays. MERTK expression was increased in 2 out of 5 osimertinib-resistant derivative cell lines; however, overexpression of MERTK alone was not sufficient to induce resistance to osimertinib treatment. In contrast, stimulation with the TAM kinase ligands GAS6 or PROS1 protected EGFRMT NSCLC cells overexpressing MERTK from osimertinib treatment, as indicated by restoration of AKT, ERK, and ribosomal S6 phosphorylation in the presence of osimertinib. Further, MERTK and its ligand PROS1 were both upregulated in xenograft tumors treated with osimertinib relative to vehicle-treated tumors. Together these data implicate activated MERTK as a mediator of resistance to osimertinib. Indeed, combined treatment with osimertinib and MRX-2843 effectively blocked PI3K-AKT and MAPK-ERK signaling and mediated synergistic inhibition of colony formation in osimertinib-resistant cells.


      Conclusion:
      MERTK inhibition may be an effective therapeutic strategy to re-sensitize osimertinib-resistant NSCLCs to EGFR TKI treatment