Advertisement

ResearchIn-Press PreviewGeneticsOncology Open Access | 10.1172/JCI194708

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

Timothy F. Burns,1 Sanja Dacic,2 Anish Chakka,3 Ethan Miller,1 Maria A. Velez,1 Ashwin Somasundaram,1 Saveri Bhattacharya,1 Autumn Gaither-Davis,1 Princey Devadassan,1 Jingxiao Jin,1 Vinod Kumar,1 Arjun Pennathur,4 Joanne Xiu,5 Matthew Oberley,5 Michael J. Glantz,6 Sonikpreet Aulakh,7 Uma R. Chandran,3 Riyue Bao,1 Curtis Tatsuoka,8 and Laura P. Stabile9

1Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Patholog, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Bioinformatics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

4Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Caris Life Sciences, Phoenix, United States of America

6Department of Neurosurgery, Penn State Health Milton S. Hershey Medical Center, Hershey, United States of America

7Department of Medical Oncology, West Virginia University, Morgantown, United States of America

8Department of Biostatistics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

9Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

Find articles by Burns, T. in: PubMed | Google Scholar

1Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Patholog, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Bioinformatics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

4Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Caris Life Sciences, Phoenix, United States of America

6Department of Neurosurgery, Penn State Health Milton S. Hershey Medical Center, Hershey, United States of America

7Department of Medical Oncology, West Virginia University, Morgantown, United States of America

8Department of Biostatistics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

9Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

Find articles by Dacic, S. in: PubMed | Google Scholar

1Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Patholog, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Bioinformatics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

4Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Caris Life Sciences, Phoenix, United States of America

6Department of Neurosurgery, Penn State Health Milton S. Hershey Medical Center, Hershey, United States of America

7Department of Medical Oncology, West Virginia University, Morgantown, United States of America

8Department of Biostatistics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

9Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

Find articles by Chakka, A. in: PubMed | Google Scholar

1Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Patholog, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Bioinformatics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

4Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Caris Life Sciences, Phoenix, United States of America

6Department of Neurosurgery, Penn State Health Milton S. Hershey Medical Center, Hershey, United States of America

7Department of Medical Oncology, West Virginia University, Morgantown, United States of America

8Department of Biostatistics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

9Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

Find articles by Miller, E. in: PubMed | Google Scholar

1Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Patholog, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Bioinformatics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

4Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Caris Life Sciences, Phoenix, United States of America

6Department of Neurosurgery, Penn State Health Milton S. Hershey Medical Center, Hershey, United States of America

7Department of Medical Oncology, West Virginia University, Morgantown, United States of America

8Department of Biostatistics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

9Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

Find articles by Velez, M. in: PubMed | Google Scholar

1Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Patholog, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Bioinformatics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

4Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Caris Life Sciences, Phoenix, United States of America

6Department of Neurosurgery, Penn State Health Milton S. Hershey Medical Center, Hershey, United States of America

7Department of Medical Oncology, West Virginia University, Morgantown, United States of America

8Department of Biostatistics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

9Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

Find articles by Somasundaram, A. in: PubMed | Google Scholar

1Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Patholog, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Bioinformatics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

4Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Caris Life Sciences, Phoenix, United States of America

6Department of Neurosurgery, Penn State Health Milton S. Hershey Medical Center, Hershey, United States of America

7Department of Medical Oncology, West Virginia University, Morgantown, United States of America

8Department of Biostatistics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

9Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

Find articles by Bhattacharya, S. in: PubMed | Google Scholar

1Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Patholog, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Bioinformatics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

4Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Caris Life Sciences, Phoenix, United States of America

6Department of Neurosurgery, Penn State Health Milton S. Hershey Medical Center, Hershey, United States of America

7Department of Medical Oncology, West Virginia University, Morgantown, United States of America

8Department of Biostatistics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

9Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

Find articles by Gaither-Davis, A. in: PubMed | Google Scholar

1Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Patholog, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Bioinformatics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

4Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Caris Life Sciences, Phoenix, United States of America

6Department of Neurosurgery, Penn State Health Milton S. Hershey Medical Center, Hershey, United States of America

7Department of Medical Oncology, West Virginia University, Morgantown, United States of America

8Department of Biostatistics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

9Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

Find articles by Devadassan, P. in: PubMed | Google Scholar

1Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Patholog, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Bioinformatics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

4Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Caris Life Sciences, Phoenix, United States of America

6Department of Neurosurgery, Penn State Health Milton S. Hershey Medical Center, Hershey, United States of America

7Department of Medical Oncology, West Virginia University, Morgantown, United States of America

8Department of Biostatistics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

9Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

Find articles by Jin, J. in: PubMed | Google Scholar

1Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Patholog, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Bioinformatics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

4Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Caris Life Sciences, Phoenix, United States of America

6Department of Neurosurgery, Penn State Health Milton S. Hershey Medical Center, Hershey, United States of America

7Department of Medical Oncology, West Virginia University, Morgantown, United States of America

8Department of Biostatistics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

9Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

Find articles by Kumar, V. in: PubMed | Google Scholar

1Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Patholog, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Bioinformatics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

4Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Caris Life Sciences, Phoenix, United States of America

6Department of Neurosurgery, Penn State Health Milton S. Hershey Medical Center, Hershey, United States of America

7Department of Medical Oncology, West Virginia University, Morgantown, United States of America

8Department of Biostatistics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

9Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

Find articles by Pennathur, A. in: PubMed | Google Scholar

1Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Patholog, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Bioinformatics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

4Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Caris Life Sciences, Phoenix, United States of America

6Department of Neurosurgery, Penn State Health Milton S. Hershey Medical Center, Hershey, United States of America

7Department of Medical Oncology, West Virginia University, Morgantown, United States of America

8Department of Biostatistics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

9Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

Find articles by Xiu, J. in: PubMed | Google Scholar

1Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Patholog, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Bioinformatics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

4Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Caris Life Sciences, Phoenix, United States of America

6Department of Neurosurgery, Penn State Health Milton S. Hershey Medical Center, Hershey, United States of America

7Department of Medical Oncology, West Virginia University, Morgantown, United States of America

8Department of Biostatistics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

9Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

Find articles by Oberley, M. in: PubMed | Google Scholar

1Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Patholog, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Bioinformatics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

4Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Caris Life Sciences, Phoenix, United States of America

6Department of Neurosurgery, Penn State Health Milton S. Hershey Medical Center, Hershey, United States of America

7Department of Medical Oncology, West Virginia University, Morgantown, United States of America

8Department of Biostatistics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

9Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

Find articles by Glantz, M. in: PubMed | Google Scholar

1Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Patholog, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Bioinformatics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

4Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Caris Life Sciences, Phoenix, United States of America

6Department of Neurosurgery, Penn State Health Milton S. Hershey Medical Center, Hershey, United States of America

7Department of Medical Oncology, West Virginia University, Morgantown, United States of America

8Department of Biostatistics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

9Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

Find articles by Aulakh, S. in: PubMed | Google Scholar

1Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Patholog, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Bioinformatics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

4Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Caris Life Sciences, Phoenix, United States of America

6Department of Neurosurgery, Penn State Health Milton S. Hershey Medical Center, Hershey, United States of America

7Department of Medical Oncology, West Virginia University, Morgantown, United States of America

8Department of Biostatistics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

9Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

Find articles by Chandran, U. in: PubMed | Google Scholar

1Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Patholog, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Bioinformatics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

4Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Caris Life Sciences, Phoenix, United States of America

6Department of Neurosurgery, Penn State Health Milton S. Hershey Medical Center, Hershey, United States of America

7Department of Medical Oncology, West Virginia University, Morgantown, United States of America

8Department of Biostatistics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

9Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

Find articles by Bao, R. in: PubMed | Google Scholar |

1Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Patholog, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Bioinformatics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

4Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Caris Life Sciences, Phoenix, United States of America

6Department of Neurosurgery, Penn State Health Milton S. Hershey Medical Center, Hershey, United States of America

7Department of Medical Oncology, West Virginia University, Morgantown, United States of America

8Department of Biostatistics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

9Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

Find articles by Tatsuoka, C. in: PubMed | Google Scholar

1Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Patholog, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Bioinformatics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

4Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Caris Life Sciences, Phoenix, United States of America

6Department of Neurosurgery, Penn State Health Milton S. Hershey Medical Center, Hershey, United States of America

7Department of Medical Oncology, West Virginia University, Morgantown, United States of America

8Department of Biostatistics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

9Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

Find articles by Stabile, L. in: PubMed | Google Scholar |

Published December 18, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI194708.
Copyright © 2025, Burns et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published December 18, 2025 - Version history
View PDF
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.

Graphical Abstract
graphical abstract
Supplemental material

View

View Supplemental Tables

Version history
  • Version 1 (December 18, 2025): In-Press Preview
Advertisement
Advertisement