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

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Abstract

Non-small cell lung cancer (NSCLC) exhibits the highest rates of brain metastases (BM) among all solid tumors and presents a significant clinical challenge. The development of novel therapeutic strategies targeting BM is clearly needed. We identified a significant enrichment of MET amplification in lung adenocarcinoma (LUAD) BM compared to primary LUAD and extracranial metastases in oncogene driver-negative patients. Of note, MET amplified BM 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 LUAD BM patients than in those without BM. MET altered BM also demonstrated unique genomic features compared to non-MET altered BM. Transcriptomic analyses revealed that in contrast to MET wildtype BM, MET amplified BM exhibited a more inflamed tumor microenvironment and displayed evidence of metabolic adaptation, particularly a reliance on glycolysis in contrast to oxidative phosphorylation in MET wildtype BM. Further, MET amplified BM demonstrated evidence of epithelial-mesenchymal transition signaling including increased expression of TWIST1. Patients with MET amplified BM had significantly shorter overall survival. These findings highlight MET amplification as a critical driver of LUAD BM, emphasizing its potential as a therapeutic target.

Authors

Timothy F. Burns, Sanja Dacic, Anish Chakka, Ethan Miller, Maria A. Velez, Ashwin Somasundaram, Saveri Bhattacharya, Autumn Gaither-Davis, Princey Devadassan, Jingxiao Jin, Vinod Kumar, Arjun Pennathur, Joanne Xiu, Matthew Oberley, Michael J. Glantz, Sonikpreet Aulakh, Uma R. Chandran, Riyue Bao, Curtis Tatsuoka, Laura P. Stabile