{"doi":"10.1172/jci150517","title":"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 (EGFRMT) 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 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.","journal":"Journal of Clinical Investigation","year":2022,"id":240230,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":46,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9507,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":276622,"name":"Justus M. Huelse","orcid":null,"position":1,"is_corresponding":false},{"id":36749,"name":"Dmitri Kireev","orcid":"0000-0001-8479-8555","position":2,"is_corresponding":false},{"id":868109,"name":"Zikang Tan","orcid":null,"position":3,"is_corresponding":false},{"id":297197,"name":"Luxiao Chen","orcid":"0000-0001-8862-4632","position":4,"is_corresponding":false},{"id":506614,"name":"Subir Goyal","orcid":"0000-0003-1737-7771","position":5,"is_corresponding":false},{"id":392225,"name":"Xiaodong Wang","orcid":"0000-0003-3293-7538","position":6,"is_corresponding":false},{"id":392226,"name":"Stephen V. Frye","orcid":"0000-0002-2415-2215","position":7,"is_corresponding":false},{"id":69837,"name":"Madhusmita Behera","orcid":"0000-0003-1121-6002","position":8,"is_corresponding":false},{"id":867412,"name":"Frank Schneider","orcid":"0000-0003-2332-3278","position":9,"is_corresponding":false},{"id":79467,"name":"Suresh S. Ramalingam","orcid":"0000-0002-0757-3106","position":10,"is_corresponding":false},{"id":70194,"name":"Taofeek K. Owonikoko","orcid":"0000-0002-7724-7728","position":11,"is_corresponding":false},{"id":304429,"name":"H. Shelton Earp","orcid":"0000-0003-1229-4619","position":12,"is_corresponding":false},{"id":275364,"name":"Deborah DeRyckere","orcid":"0000-0002-7457-9006","position":13,"is_corresponding":false},{"id":275365,"name":"Douglas K. Graham","orcid":"0000-0002-6201-6900","position":14,"is_corresponding":false},{"id":867411,"name":"Dan Yan","orcid":"0000-0001-7531-5814","position":0,"is_corresponding":true}],"reference_count":72,"raw_metadata":null,"created_at":"2026-07-19T00:22:46.554789Z","pmid":"35708914","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}