MERTK activation drives osimertinib resistance in EGFR-mutant non–small cell lung cancer

Abstract

Acquired resistance is inevitable in non–small cell lung cancers (NSCLCs) treated with osimertinib (OSI), and the mechanisms are not well defined. The MERTK ligand GAS6 promoted downstream oncogenic signaling in EGFR -mutated ( EGFR MT ) NSCLC cells treated with OSI, suggesting a role for MERTK activation in OSI resistance. Indeed, treatment with MRX-2843, a first-in-class MERTK kinase inhibitor, resensitized GAS6-treated NSCLC cells to OSI. Both GAS6 and EGF stimulated downstream PI3K/AKT and MAPK/ERK signaling in parental cells, but only GAS6 activated these pathways in OSI-resistant (OSIR) derivative cell lines. Functionally, OSIR cells were more sensitive to MRX-2843 than parental cells, suggesting acquired dependence on MERTK signaling. Furthermore, MERTK and/or its ligands were dramatically upregulated in EGFR MT tumors after treatment with OSI in both xenograft models and patient samples, consistent with induction of autocrine/paracrine MERTK activation. Moreover, treatment with MRX-2843 in combination with OSI, but not OSI alone, provided durable suppression of tumor growth in vivo, even after treatment was stopped. These data identify MERTK as a driver of bypass signaling in treatment-naive and EGFR MT -OSIR NSCLC cells and predict that MRX-2843 and OSI combination therapy will provide clinical benefit in patients with EGFR MT NSCLC.

Protective Role of MerTK in Diabetic Peripheral Neuropathy via Inhibition of the NF-κB Signaling Pathway

“…MerTK is expressed in both immune and non-immune cells and is involved in inflammation, metabolism, and vascular homeostasis [20]. Previous studies have indicated that MerTK protects against liver fibrosis and cancer [21][22][23]. The expression of MerTK in 13 the sciatic nerve and serum of rats was detected via immunohistochemistry, immunofluorescence, western blotting, and ELISA methods in our study, which showed that MerTK was upregulated in the T2DM and DPN groups, and the expression of MerTK was significantly increased in the DPN group than in the CON and T2DM groups, which is consistent with the results of our previous study [10].…”

Glycolytic Genes Predict Immune Status and Prognosis Non‐Small‐Cell Lung Cancer Patients with Radiotherapy and Chemotherapy

“…MERTK inhibitors have been confirmed to be used in combination with radiotherapy or chemotherapy in glioma, NSCLC, head and neck squamous cell carcinoma, and other tumors to achieve better efficacy [30][31][32]. In addition, ERO1A, PKP2, and MERTK have been proved to promote the progress and drug resistance of NSCLC by enhancing the activation of tumor and PI3K, EGFR, and other signal pathways [33][34][35]. In this study, we identified the good prognosis prediction effect of this risk model and confirmed this prediction effect using chemotherapy patients in the GSE42127 dataset as a validation cohort.…”

Exosomal Non-Coding RNAs: Novel Regulators of Macrophage-Linked Intercellular Communication in Lung Cancer and Inflammatory Lung Diseases

“…Exosomal LINC00313 produced by lung cancer cells also promotes M2 polarization of macrophages and lung tumor growth in vivo [ 75 ]. Advanced NSCLC is frequently treated with osimertinib, an irreversible third-generation tyrosine kinase inhibitor (TKI) of the epidermal growth factor receptor (EGFR) [ 76 ]. LncRNA SOX2 overlapping transcript (SOX2-OT) is concentrated in exosomes isolated from H1975 cells.…”