MET alterations are enriched in lung adenocarcinoma brain metastases, defining a distinct biologic subtype.

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.