Abstract 2636: Targeting the HGF/MET/TWIST1 pathway in lung adenocarcinoma brain metastases
Authors: Xiaxuan Wu, Charitha Marni, Veronica Zhang, Prarthana Mocherla, Jacob George, Purva Rumde, Rohan K. Goyal, Lora H. Rigatti, Princey Devadassan, Autumn Gaither Davis, Timothy F. Burns, Laura P. Stabile
Journal: Cancer Research (2025)

Abstract Lung adenocarcinoma (LUAD) is the most common primary tumor to metastasize to the brain, with ∼40% of patients developing brain metastases (BM) which is associated with poor prognosis. No brain specific targeted therapies currently exist, highlighting the need for novel treatments. We identified a significant enrichment of MET amplification in LUAD BM compared to primary LUAD and liver metastases. MET, a tyrosine kinase receptor, and its ligand hepatocyte growth factor (HGF), mediate proliferation, epithelial-mesenchymal transition (EMT), angiogenesis, and metastasis. We have found that MET-driven tumorigenesis is dependent on the EMT transcription factor, TWIST1, which is regulated by the HGF/MET pathway and is overexpressed in LUAD BM. These findings led us to hypothesize that the HGF/MET/TWIST1 axis is a potential therapeutic target for LUAD BM. To examine the role of the HGF/MET/TWIST1 pathway in LUAD BM, we utilized an ex vivo organotypic brain slice model. Using a patient derived LUAD cell line pair, H2073 (primary tumor, MET wildtype; WT) and H1993 (metastasis, MET amplified), we found increased brain colonization with the MET amplified H1993 cells. In addition, HGF promoted brain colonization of MET WT H2073 cells, while the MET inhibitor capmatinib reduced brain colonization of MET amplified H1993 cells. Similarly, using our murine syngeneic LUAD lines, FVBW-17 (MET WT) and FVB-HGF (HGF overexpression; OE), we found that HGF OE led to increased brain colonization. Additionally, conditioned medium (CM) from H1993 cells increased astrocyte migration compared to CM from MET WT H2073 cells. Capmatinib reduced H1993 CM-mediated astrocyte migration, while HGF induced H2073 CM-mediated astrocyte migration. Further, these HGF/MET driven processes appeared to be TWIST1 dependent as TWIST1 inhibition with harmine decreased brain colonization in both MET amplified H1993 and MET mutant H1437 cells, and inhibited astrocyte migration induced by CM from H1993. We next examined the role of the HGF/MET/TWIST1 pathway on BM in vivo. Using an intracardiac injection metastasis model, we observed a higher frequency of BM in HGF OE mice compared to WT SCID mice in all LUAD lines assessed. In WT SCID mice, time to BM development was significantly shorter in mice injected with MET amplified cells compared to MET WT cells. Further, BM was accelerated in HGF OE mice compared to WT mice injected with H2073 MET WT cells. In syngeneic LUAD models, 40% of mice injected with HGF OE cells developed BM versus 0% of mice injected with WT cells. Moreover, orthotopic intracranial injections showed a two-fold faster growth rate of HGF OE cells compared to WT cells. Finally, capmatinib or harmine treatment in mice with BM led to BM disappearance, with harmine showing a sustained effect lasting over three months after end of treatment. These findings suggest that targeting the HGF/MET/TWIST1 axis may be an effective treatment strategy for MET amplified LUAD BM. Citation Format: Xiaxuan Wu, Charitha Marni, Veronica Zhang, Prarthana Mocherla, Jacob George, Purva Rumde, Rohan K. Goyal, Lora H. Rigatti, Princey Devadassan, Autumn Gaither Davis, Timothy F. Burns, Laura P. Stabile. Targeting the HGF/MET/TWIST1 pathway in lung adenocarcinoma brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2636.