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

• Type of Material: Article
• Authors: Dan Yan, Emory University; Justus M Huelse, Emory University; Dmitri Kireev, University of North Carolina; Zikang Tan, Emory University; Luxiao Chen, Emory University; Subir Goyal, Emory University; Xiaodong Wang, University of North Carolina; Stephen Frye, University of North Carolina; Madhusmita Behera, Emory University; Frank Schneider, Emory University; Suresh Ramalingam, Emory University; Taofeek Owonikoko, Emory University; Shelton H Earp, UNC Lineberger Comprehensive Cancer Center, Chapel Hill; Deborah DeRyckere, Emory University; Douglas Graham, Emory University
• Language: English
• Date: 2022-08-01
• Publisher: AMER SOC CLINICAL INVESTIGATION INC
• Publication Version: Final Published Version
• Copyright Statement: © 2022, Yan et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1172/JCI150517
• Title of Journal or Parent Work: JOURNAL OF CLINICAL INVESTIGATION
• Volume: 132
• Issue: 15
• Grant/Funding Information: The data included in this manuscript are the major data used for the funded Emory Lung Cancer Spore (P50CA217691) of Project 2.
• Keywords: SURVIVAL; INHIBITORS; Medicine, Research & Experimental; Life Sciences & Biomedicine; THERAPY; RECEPTOR-TYROSINE KINASE; AXL KINASE; Research & Experimental Medicine; MUTATIONS; GEFITINIB; MODELS; DOCETAXEL; MOLECULAR-DYNAMICS; Science & Technology
• Research Categories: Health Sciences, Oncology; Biology, Biostatistics; Health Sciences, Pharmacology

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 (EGFRMT) NSCLC cells treated with OSI, suggesting a role for MERTK activation in OSI resistance. Indeed, treatment with MRX-2843, a firstin- 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 EGFRMT 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 EGFRMT-OSIR NSCLC cells and predict that MRX-2843 and OSI combination therapy will provide clinical benefit in patients with EGFRMT NSCLC.