Kinase-Targeted Therapies for Glioblastoma

Abstract

Protein phosphorylation and dephosphorylation are key mechanisms that regulate cellular activities. The addition or removal of phosphate groups by specific enzymes, known as kinases and phosphatases, activates or inhibits many enzymes and receptors involved in various cell signaling pathways. Dysregulated activity of these enzymes is associated with various diseases, predominantly cancers. Synthetic and natural single- and multiple-kinase inhibitors are currently being used as targeted therapies for different tumors, including glioblastoma. Glioblastoma IDH-wild-type is the most aggressive brain tumor in adults, with a median overall survival of 15 months. The great majority of glioblastoma patients present mutations in receptor tyrosine kinase (RTK) signaling pathways responsible for tumor initiation and/or progression. Despite this, the multi-kinase inhibitor regorafenib has only recently been approved for glioblastoma patients in some countries. In this review, we analyze the history of kinase inhibitor drugs in glioblastoma therapy.

Keywords: glioblastoma; kinase inhibitor; therapy.

Figure 1

Histopathological features of glioblastoma and current therapies. Primary glioblastoma is characterized by large heterogeneity, high cellular proliferative index, wide necrotic areas, and massive angiogenesis. Standard therapy is based on massive surgery followed by adjuvant radiation and chemotherapy with the alkylating agent temozolomide. The presence of therapy-resistant glioma stem cells (GSCs) characterizes recurrent glioblastoma. Therapeutic options for relapsed tumors are poor.

Figure 2

Kinase receptors and their inhibitors. Kinase inhibitors target different receptors affecting multiple cellular pathways involved in the regulation of key biological processes.