{"doi":"10.1084/jem.20240435","title":"Inhibition of hTERT/telomerase/telomere mediates therapeutic efficacy of osimertinib in EGFR mutant lung cancer","abstract":"The inevitable acquired resistance to osimertinib (AZD9291), an FDA-approved third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI) for the treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR activating or T790M resistant mutations, limits its long-term clinical benefit. Telomere maintenance via telomerase reactivation is linked to uncontrolled cell growth and is a cancer hallmark and an attractive cancer therapeutic target. Our effort toward understanding the action mechanisms, including resistance mechanisms, of osimertinib has led to the identification of a novel and critical role in maintaining c-Myc-dependent downregulation of hTERT, a catalytic subunit of telomerase, and subsequent inhibition of telomerase/telomere and induction of telomere dysfunction in mediating therapeutic efficacy of osimertinib. Consequently, osimertinib combined with the telomere inhibitor, 6-Thio-dG, which is currently tested in a phase II trial, effectively inhibited the growth of osimertinib-resistant tumors, regressed EGFRm NSCLC patient-derived xenografts, and delayed the emergence of acquired resistance to osimertinib, warranting clinical validation of this strategy to manage osimertinib acquired resistance.","journal":"The Journal of Experimental Medicine","year":2024,"id":432465,"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":15,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9488,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":681895,"name":"Karin A. Vallega","orcid":"0000-0003-2237-8509","position":1,"is_corresponding":false},{"id":1237033,"name":"Dongsheng Wang","orcid":"0000-0002-9830-6045","position":2,"is_corresponding":false},{"id":1237034,"name":"Zihan Quan","orcid":"0009-0005-7261-3644","position":3,"is_corresponding":false},{"id":355150,"name":"Songqing Fan","orcid":"0000-0002-1486-9909","position":4,"is_corresponding":false},{"id":651877,"name":"Qiming Wang","orcid":"0000-0003-3217-1077","position":5,"is_corresponding":false},{"id":434077,"name":"Ticiana Leal","orcid":"0000-0002-3735-9063","position":6,"is_corresponding":false},{"id":79467,"name":"Suresh S. Ramalingam","orcid":"0000-0002-0757-3106","position":7,"is_corresponding":false},{"id":254878,"name":"Shi‐Yong Sun","orcid":"0000-0002-0117-8826","position":8,"is_corresponding":false},{"id":577405,"name":"Zhen Chen","orcid":"0000-0003-3949-5744","position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":null,"created_at":"2026-07-19T01:59:35.267142Z","pmid":"39297884","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":[]}