Targeting MET in non-small cell lung cancer brain metastases: from molecular mechanism to precision therapy

Brain metastases (BM) remain a major cause of morbidity and treatment failure in non-small cell lung cancer (NSCLC). Among actionable pathways, mesenchymal–epithelial transition factor (MET) is clinically consequential not only as an oncogenic driver in a molecular subset of tumors but also as a convergent bypass route that mediates acquired resistance in the much larger EGFR-mutant population, making MET an important focus in the context of intracranial progression under targeted-therapy pressure. Available genomic datasets suggest a distinct distribution of MET alterations in BM, with MET amplification relatively enriched in intracranial lesions while MET exon 14 skipping is less frequent than in primary tumors. Mechanistically, MET signaling supports key steps of brain colonization, including trans-endothelial invasion across the blood–brain barrier, epithelial–mesenchymal transition, and context-dependent adaptation to the brain microenvironments; evidence from other tumor types further reinforces these pro-metastatic programs. Precision management requires robust molecular profiling: RNA-based next-generation sequencing improves detection of splice events such as MET exon 14 skipping, while tissue and liquid biopsy (including cerebrospinal fluid–derived ctDNA when feasible) can capture intracranial clonal evolution. Clinically, selective MET tyrosine kinase inhibitors (e.g., capmatinib, tepotinib) have demonstrated intracranial activity in small BM subgroups, and combination strategies, most notably dual EGFR/MET blockade using MET inhibitors or EGFR/MET-directed antibodies, are emerging as rational approaches for MET-driven resistance, although heterogeneous CNS endpoints and prior brain-directed therapies limit cross-study comparability. MET is an actionable vulnerability in NSCLC-BM and should be considered beyond treatment-naïve MET-driven disease, extending to patients with acquired MET amplification during EGFR-TKI exposure. BM-dedicated trials with standardized intracranial endpoints and integrated pharmacokinetic/pharmacodynamic assessment are needed to optimize patient selection, sequencing, and resistance-informed combination strategies.