Aberrant MET Receptor Tyrosine Kinase Signaling in Glioblastoma: Targeted Therapy and Future Directions - Review

Sep 21, 2026

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Brain tumors represent a heterogeneous group of neoplasms characterized by high aggressiveness and poor outcomes. Despite recent therapeutic advances, treatment of glioblastoma (GBM), an aggressive primary brain tumor with resistance to therapy, remains a major challenge. Dysregulated receptor tyrosine kinases (RTKs) drive many cancers and offer actionable targets. The Met RTK and its HGF/SF axis regulate key signaling for epithelial-to-mesenchymal transition (EMT), while aberrant Met activity promotes GBM proliferation, survival, invasion, and chemoresistance through cancer stem-like cell survival and DNA repair upregulation. This review summarizes MET dysregulation mechanisms in GBM and evaluates preclinical and clinical MET-targeted therapies.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages18

Reading Time45 min

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Abstract

Introduction

cells Review Aberrant MET Receptor Tyrosine Kinase Signaling in Glioblastoma: Targeted Therapy and Future Directions Abdulhameed Al-Ghabkari 1, Bruce Huang 1,2 and Morag Park 1,2,3,4, * Citation: Al-Ghabkari, A.; Huang, B.; Park, M. Aberrant MET Receptor Tyrosine Kinase Signaling in Glioblastoma: Targeted Therapy and Future Directions. Cells 2024, 13, 218 . [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)cells13030218 Academic Editors: Georg Karpel-Massler, Mike-Andrew Westhoff, Ritva Tikkanen and Laszlo Buday Received: 8 November 2023 Revised: 27 November 2023 Accepted: 12 January 2024 Published: 25 January 2024 Copyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . 1 Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada; [abdulhameed.alghabkari@mcgill.ca](abdulhameed.alghabkari@mcgill.ca) (A.A.-G.); [bruce.huang@mail.mcgill.ca](bruce.huang@mail.mcgill.ca) (B.H.) 2 Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada 3 Department of Oncology, McGill University, Montreal, QC H4A 3T2, Canada 4 Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada * [Correspondence: morag.park@mcgill.ca](Correspondence: morag.park@mcgill.ca) Abstract: Brain tumors represent a heterogeneous group of neoplasms characterized by a high degree of aggressiveness and a poor prognosis. Despite recent therapeutic advances, the treatment of brain tumors, including glioblastoma (GBM), an aggressive primary brain tumor associated with poor prognosis and resistance to therapy, remains a significant challenge. Receptor tyrosine kinases (RTKs) are critical during development and in adulthood. Dysregulation of RTKs through activating mutations and gene amplification contributes to many human cancers and provides attractive therapeutic targets for treatment. Under physiological conditions, the Met RTK, the hepatocyte growth factor/scatter factor (HGF/SF) receptor, promotes fundamental signaling cascades that modulate epithelial-tomesenchymal transition (EMT) involved in tissue repair and embryogenesis. In cancer, increased Met activity promotes tumor growth and metastasis by providing signals for proliferation, survival, and migration/invasion. Recent clinical genomic studies have unveiled multiple mechanisms by which MET is genetically altered in GBM, including focal amplification, chromosomal rearrangements generating gene fusions, and a splicing variant mutation (exon 14 skipping, METex14del) . Notably, MET overexpression contributes to chemotherapy resistance in GBM by promoting the survival of cancer stem-like cells. This is linked to distinctive Met-induced pathways, such as the upregulation of DNA repair mechanisms, which can protect tumor cells from the cytotoxic effects of chemotherapy. The development of MET-targeted therapies represents a major step forward in the treatment of brain tumours. Preclinical studies have shown that MET-targeted therapies (monoclonal antibodies or small molecule inhibitors) can suppress growth and invasion, enhancing the efficacy of conventional therapies. Early-phase clinical trials have demonstrated promising results with MET-targeted therapies in improving overall survival for patients with recurrent GBM. However, challenges remain, including the need for patient stratification, the optimization of treatment regimens, and the identification of mechanisms of resistance. This review aims to highlight the current understanding of mechanisms underlying MET dysregulation in GBM. In addition, it will focus on the ongoing preclinical and clinical assessment of therapies targeting MET d

FAQs

What role does MET receptor signaling play in glioblastoma progression?

MET activity supports GBM growth and metastasis by delivering signals for proliferation, survival, and migration/invasion. MET overexpression also contributes to chemotherapy resistance.

What genetic mechanisms can alter MET in glioblastoma?

MET can be altered in GBM through focal amplification, chromosomal rearrangements that create gene fusions, and splicing mutations such as exon 14 skipping (METex14del).

What are the main challenges for MET-targeted therapies in recurrent GBM?

Key challenges include patient stratification, optimizing treatment regimens, and identifying mechanisms of resistance despite promising early-phase clinical results.

Sep 21, 2026

Uploaded by Himbo