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The development of novel therapeutic strategies targeting BMs is clearly needed. We identified a significant enrichment of\n                    <jats:italic>MET<\/jats:italic>\n                    amplification in lung adenocarcinoma (LUAD) BMs compared with primary LUAD and extracranial metastases in oncogene driver\u2013negative patients. Of note,\n                    <jats:italic>MET<\/jats:italic>\n                    -amplified BMs were responsive to MET inhibitors in vivo, including models with acquired\n                    <jats:italic>MET<\/jats:italic>\n                    amplification at the time of metastasis.\n                    <jats:italic>MET<\/jats:italic>\n                    alterations (amplifications and\/or mutations) were also more frequently detected in circulating tumor DNA from patients with LUAD BMs than in those without BMs.\n                    <jats:italic>MET-<\/jats:italic>\n                    altered BMs also demonstrated unique genomic features compared with non\u2013\n                    <jats:italic>MET-<\/jats:italic>\n                    altered BMs. Transcriptomic analyses revealed that in contrast to\n                    <jats:italic>MET<\/jats:italic>\n                    WT BMs,\n                    <jats:italic>MET<\/jats:italic>\n                    -amplified BMs exhibited a more inflamed tumor microenvironment and displayed evidence of metabolic adaptation, particularly a reliance on glycolysis in contrast to OXPHOS in\n                    <jats:italic>MET<\/jats:italic>\n                    WT BMs. Furthermore,\n                    <jats:italic>MET<\/jats:italic>\n                    -amplified BMs demonstrated evidence of epithelial-mesenchymal transition signaling, including increased expression of TWIST1. Patients with\n                    <jats:italic>MET<\/jats:italic>\n                    -amplified BMs had significantly shorter overall survival. These findings highlight\n                    <jats:italic>MET<\/jats:italic>\n                    amplification as a critical driver of LUAD BMs, emphasizing its potential as a therapeutic target.\n                  <\/jats:p>","DOI":"10.1172\/jci194708","type":"journal-article","created":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T17:01:30Z","timestamp":1766077290000},"source":"Crossref","is-referenced-by-count":3,"title":["MET alterations are enriched in lung adenocarcinoma brain metastases, defining a distinct biologic subtype"],"prefix":"10.1172","volume":"136","author":[{"given":"Timothy F.","family":"Burns","sequence":"first","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Medicine, and"},{"name":"Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA."},{"name":"UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanja","family":"Dacic","sequence":"additional","affiliation":[{"name":"Department of Pathology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anish","family":"Chakka","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ethan","family":"Miller","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria A.","family":"Velez","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashwin","family":"Somasundaram","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saveri","family":"Bhattacharya","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Autumn","family":"Gaither-Davis","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Princey","family":"Devadassan","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingxiao","family":"Jin","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinod","family":"Kumar","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arjun","family":"Pennathur","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanne","family":"Xiu","sequence":"additional","affiliation":[{"name":"Caris Life Sciences, Phoenix, Arizona, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Oberley","sequence":"additional","affiliation":[{"name":"Caris Life Sciences, Phoenix, Arizona, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Glantz","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Penn State Health Milton S. 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