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

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-to-mesenchymal 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 dysregulation in GBM.

Keywords: MET exon 14 skipping; MET-targeted therapies; glioblastoma (GBM); hepatocyte growth factor/scatter factor (HGF/SF).

Figure 1

Met structure and function. Following HGF binding to MET triggers MET dimerization (Met is illustrated as monomer to simplify the model) and phosphorylation of Met within the activation loops, leading to activation of the receptor and followed by subsequent phosphorylation events in the c-terminal domain (Y1349 and Y1356) that enables Met to engage with a number of downstream signaling pathways, such as cytoskeletal remodelling, cell proliferation, and cell survival through coupling Met with multiple adaptor proteins, such as growth factor receptor-bound protein 2 (Grb2), Src homology 2 domain-containing (Shc), and the p85 subunit of phosphoinositide 3-kinases (PI3K). In addition, Grb2 recruits the docking protein Grb2-associated-binding protein 1 (Gab1), which can recruit other key signaling elements, such as tyrosine phosphatase SRC homology 2 domain-containing phosphatase 2 (SHP2), CRK, and PAK4. Additionally, Grb2 serves the crucial function of recruiting the c-Cbl ubiquitin ligase, which acts as a negative regulator of Met.

Figure 2

Mechanisms of MET oncogenic activation in GBM. (A) Physiologically, HGF-METet interaction promotes dimerization and potentially oligomerization of the Met receptor and subsequent trans-phosphorylation of tyrosine residues Y1234 and Y1235 within its kinase domain, subsequently engaging Met with downstream signaling pathways. (B) Focal MET amplification is associated with high MET expression and enhances ligand-independent oncogenic activity. (C) Gene rearrangements and chromosomal translocations result in constitutive activation of the fusion proteins that typically self-dimerize in a ligand-independent manner, leading to oncogenic activity. (D) Loss of the direct Cbl-TKB-binding site via the loss of exon 14 is associated with reduced ubiquitination, decreased degradation, and sustained Met activation following HGF stimulation, leading to increased oncogenic activity.