Receptor tyrosine kinases as druggable targets in glioblastoma: Do signaling pathways matter?

Abstract

Glioblastoma (GBM) is the most malignant primary brain tumor without effective therapies. Since bevacizumab was FDA approved for targeting vascular endothelial growth factor receptor 2 (VEGFR2) in adult patients with recurrent GBM, targeted therapy against receptor tyrosine kinases (RTKs) has become a new avenue for GBM therapeutics. In addition to VEGFR, the epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), hepatocyte growth factor receptor (HGFR/MET), and fibroblast growth factor receptor (FGFR) are major RTK targets. However, results from clinical Phase II/III trials indicate that most RTK-targeting therapeutics including tyrosine kinase inhibitors (TKIs) and neutralizing antibodies lack clinical efficacy, either alone or in combination. The major challenge is to uncover the genetic RTK alterations driving GBM initiation and progression, as well as to elucidate the mechanisms toward therapeutic resistance. In this review, we will discuss the genetic alterations in these five commonly targeted RTKs, the clinical trial outcomes of the associated RTK-targeting therapeutics, and the potential mechanisms toward the resistance. We anticipate that future design of new clinical trials with combination strategies, based on the genetic alterations within an individual patient’s tumor and mechanisms contributing to therapeutic resistance after treatment, will achieve durable remissions and improve outcomes in GBM patients

Clinical Application of Comprehensive Genomic Profiling Tests for Diffuse Gliomas

“…However, the total proportion of mutations in the FGFR family is not negligible (16%). Therefore, pan-FGFR inhibitors might effectively treat GBMs [22][23][24]. The frequency of BRAF mutation in our study is higher than that reported in previous reports because patients must have CGPT to attend a clinical trial using BRAF inhibitors after the detection of BRAF V600E using immunohistochemistry.…”

Neurotransmitters: Potential Targets in Glioblastoma

“…PIK3CA mutation can encode a protein that antagonizes PTEN in the PI3K/Akt pathway [ 114 ]. Researchers have summarized the potential mechanisms for resistance, mainly focusing on targeting RTKs [ 104 , 115 ].…”

Tau Protein as Therapeutic Target for Cancer? Focus on Glioblastoma

“…In GBM, Fyn was found to be overexpressed in patient samples relative to both normal brain and all other tumors, with varying patterns of expression [ 192 , 203 ]. This kinase has also been shown to be downstream of the commonly mutated RTKs in GBM, such as EGFR, PDGFR, and c-MET [ 144 ]. In addition, genetic and pharmacologic inhibitions of Fyn block EGFR-dependent motility and tumor growth both in vitro and in vivo [ 192 ].…”