Abstract 4765: MERTK is a potential therapeutic target in osimertinib-resistant non-small cell lung cancer

Abstract

Abstract 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 in the international FLAURA trial. 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 inhibitor with dual MERTK and FLT3 activity, which is currently in Phase I clinical trials. Here, we report upregulation of MERTK and its ligand PROS1 in xenograft tumors derived from the EGFRMT H4006 NSCLC cell line and treated with osimertinib relative to vehicle-treated tumors. MERTK expression was also increased in osimertinib-resistant derivatives of the H4006 and H4011 cell lines generated by culture in escalating doses of osimertinib. However, overexpression of exogenous MERTK in H4006 cells was not sufficient to confer osimertinib resistance. In contrast, stimulation with TAM kinase ligands GAS6 or PROS1 protected H4006 cells from osimertinib treatment, as indicated by restoration of AKT, ERK, and ribosomal S6 phosphorylation in the presence of osimertinib. Together these data implicate 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 H4006 cells. Thus, MERTK inhibition may be an effective therapeutic strategy to re-sensitize osimertinib-resistant NSCLCs to EGFR TKI treatment. Citation Format: Dan Yan, Justus Huelse, Rebecca Parker, Xiaodong Wang, Stephen V. Frye, H. Shelton Earp, Deborah DeRyckere, Douglas Graham. MERTK is a potential therapeutic target in osimertinib-resistant non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4765.