{"doi":"10.1172/jci194708","title":"MET alterations are enriched in lung adenocarcinoma brain metastases, defining a distinct biologic subtype","abstract":"Non-small cell lung cancer exhibits the highest rates of brain metastases (BMs) among all solid tumors, presenting a major clinical challenge. The development of novel therapeutic strategies targeting BMs is clearly needed. We identified a significant enrichment of MET amplification in lung adenocarcinoma (LUAD) BMs compared with primary LUAD and extracranial metastases in oncogene driver-negative patients. Of note, MET-amplified BMs were responsive to MET inhibitors in vivo, including models with acquired MET amplification at the time of metastasis. MET alterations (amplifications and/or mutations) were also more frequently detected in circulating tumor DNA from patients with LUAD BMs than in those without BMs. MET-altered BMs also demonstrated unique genomic features compared with non-MET-altered BMs. Transcriptomic analyses revealed that in contrast to MET WT BMs, MET-amplified BMs exhibited a more inflamed tumor microenvironment and displayed evidence of metabolic adaptation, particularly a reliance on glycolysis in contrast to OXPHOS in MET WT BMs. Furthermore, MET-amplified BMs demonstrated evidence of epithelial-mesenchymal transition signaling, including increased expression of TWIST1. Patients with MET-amplified BMs had significantly shorter overall survival. These findings highlight MET amplification as a critical driver of LUAD BMs, emphasizing its potential as a therapeutic target.","journal":"Journal of Clinical Investigation","year":2025,"id":537599,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9617,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":226189,"name":"Sanja Đačić","orcid":"0000-0003-4197-3354","position":1,"is_corresponding":false},{"id":1163129,"name":"Anish Bhaswanth Chakka","orcid":"0000-0002-1095-1817","position":2,"is_corresponding":false},{"id":234525,"name":"Ethan Miller","orcid":null,"position":3,"is_corresponding":false},{"id":557788,"name":"Maria A. Velez","orcid":"0000-0001-5197-4719","position":4,"is_corresponding":false},{"id":258579,"name":"Ashwin Somasundaram","orcid":"0000-0003-3167-406X","position":5,"is_corresponding":false},{"id":1372555,"name":"Saveri Bhattacharya","orcid":null,"position":6,"is_corresponding":false},{"id":1345429,"name":"Autumn Gaither‐Davis","orcid":null,"position":7,"is_corresponding":false},{"id":1423821,"name":"Princey Devadassan","orcid":null,"position":8,"is_corresponding":false},{"id":1096811,"name":"Jingxiao Jin","orcid":"0000-0002-4029-650X","position":9,"is_corresponding":false},{"id":298511,"name":"Vinod Kumar","orcid":"0000-0002-1510-8132","position":10,"is_corresponding":false},{"id":802075,"name":"Arjun Pennathur","orcid":"0000-0001-7937-7991","position":11,"is_corresponding":false},{"id":254337,"name":"Joanne Xiu","orcid":"0000-0001-8744-5827","position":12,"is_corresponding":false},{"id":19999,"name":"Matthew J. Oberley","orcid":"0000-0001-6419-2513","position":13,"is_corresponding":false},{"id":1423822,"name":"Michael J. Glantz","orcid":null,"position":14,"is_corresponding":false},{"id":1186993,"name":"Sonikpreet Aulakh","orcid":"0000-0001-7150-5805","position":15,"is_corresponding":false},{"id":64723,"name":"Uma Chandran","orcid":"0000-0002-0817-9880","position":16,"is_corresponding":false},{"id":35765,"name":"Riyue Bao","orcid":"0000-0002-6105-1704","position":17,"is_corresponding":false},{"id":67977,"name":"Curtis Tatsuoka","orcid":"0000-0001-9991-4440","position":18,"is_corresponding":false},{"id":378399,"name":"Laura P. Stabile","orcid":"0000-0002-1822-2707","position":19,"is_corresponding":false},{"id":1063406,"name":"Timothy F. Burns","orcid":"0000-0002-8685-3762","position":0,"is_corresponding":true}],"reference_count":107,"raw_metadata":null,"created_at":"2026-07-19T02:52:12.997494Z","pmid":"41411048","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":[]}