MET in glioma: signaling pathways and targeted therapies

Abstract

Gliomas represent the most common type of malignant brain tumor, among which, glioblastoma remains a clinical challenge with limited treatment options and dismal prognosis. It has been shown that the dysregulated receptor tyrosine kinase (RTK, including EGFR, MET, PDGFRα, ect.) signaling pathways have pivotal roles in the progression of gliomas, especially glioblastoma. Increasing evidence suggests that expression levels of the RTK MET and its specific stimulatory factors are significantly increased in glioblastomas compared to those in normal brain tissues, whereas some negative regulators are found to be downregulated. Mutations in MET, as well as the dysregulation of other regulators of cross-talk with MET signaling pathways, have also been identified. MET and its ligand hepatocyte growth factor (HGF) play a critical role in the proliferation, survival, migration, invasion, angiogenesis, stem cell characteristics, and therapeutic resistance and recurrence of glioblastomas. Therefore, combined targeted therapy for this pathway and associated molecules could be a novel and attractive strategy for the treatment of human glioblastoma. In this review, we highlight progress made in the understanding of MET signaling in glioma and advances in therapies targeting HGF/MET molecules for glioma patients in recent years, in addition to studies on the expression and mutation status of MET.

<p>Aptamer-Conjugated Gold Nanoparticles Targeting Epidermal Growth Factor Receptor Variant III for the Treatment of Glioblastoma</p>

“…It is widely accepted that the inhibition of EGFR suppresses tumor cell proliferation and invasion in GBM. [35][36][37] Consistent with these findings, our manuscript also demonstrates that 24 hr treatment with U2-AuNP could significantly reduce the phosphorylation level of EGFRvIII. To better understand the mechanism of U2-AuNP in GBM, we detected DNA damage and repair-related pathways.…”

Comprehensive review of targeted therapy for colorectal cancer

“…About the pathway Hepatocyte growth factor (HGF) and the receptor tyrosine kinase known as mesenchymal-epithelial transition factor (c-MET or MET) encoded by the MET proto-oncogene play vital roles in tumor proliferation, survival, metastasis, and acquired drug resistance. [240][241][242][243][244] This signaling pathway was first discovered from TPR-MET fusion genes (translocated promoter region locus on chromosome 1 and MET sequence on chromosome 7) of a human osteosarcoma cell line in the 1980s, when HGF was also named scatter factor because it was initially isolated from rat platelets responsible for epithelial dispersal in organ healing and regeneration. [245][246][247][248] HGF is secreted mostly from mesenchymal tissues and is currently the only known ligand for MET.…”

HGF/MET Signaling in Malignant Brain Tumors

“…Because these genetic alterations are so common, current classifications of gliomas, spearheaded by scientific discovery and adopted by the World Health Organization (WHO), have taken into account the IDH mutation status and have come up with three distinct categories of classification based on this genetic property: (1) IDH mutated with chromosome 1p/19q co-deleted; (2) IDH mutated without chromosome 1p/19q co-deleted; and (3) IDH wild-type [ 73 ]. Other gene amplifications or mutations have included RTK/RAS/PI3K, TP53 , ATRX loss, and RB signaling pathways [ 74 ]. IDH mutations are seen in gliomas such as astrocytomas and oligodendrogliomas whereas IDH wild-type is present 90% of the time in glioblastomas [ 51 ].…”

“…Aside from IDH mutations, which exist in about 10% of GBMs, there are three additional commonly deregulated pathways in glioblastoma: p53, retinoblastoma (RB), and RTK. In this context, the most commonly mutated one is the RTK/PI3K pathway, and there is approximately 88% of glioblastoma samples that harbor at least one genetic event in this core pathway [ 74 ]. MET is one of the deregulated RTKs, which promote malignant phenotypes in GBM.…”

“…It was created in an effort to overcome the obstacles of non-specific agnostic activity that can occur when divalent antibodies are used. It competes with HGF for binding to MET [ 74 ] and has been demonstrated to inhibit glioblastoma growth in preclinical testing [ 113 ]. MetMAb has been used in conjunction with bevacizumab but has not demonstrated effective therapy in a phase III clinical trial in lung cancer [ 114 ].…”