Mutational profiling of kinases in glioblastoma
Fonnet E Bleeker1, Simona Lamba, Carlo Zanon
1Department of Oncology, University of Torino, SP 142, Km 3,95, Candiolo, Torino, 10060, Italy; Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Torino, Italy. f.e.bleeker@amc.uva.nl.
Background:
Glioblastoma is a highly malignant brain tumor for which no cure is available. To identify new therapeutic targets, we performed a mutation analysis of kinase genes in glioblastoma.
Methods:
Database mining and a literature search identified 76 kinases that have been found to be mutated at least twice in multiple cancer types before. Among those we selected 34 kinase genes for mutation analysis. We also included IDH1, IDH2, PTEN, TP53 and NRAS, genes that are known to be mutated at considerable frequencies in glioblastoma. In total, 174 exons of 39 genes in 113 glioblastoma samples from 109 patients and 16 high-grade glioma (HGG) cell lines were sequenced.
Results:
Our mutation analysis led to the identification of 148 non-synonymous somatic mutations, of which 25 have not been reported before in glioblastoma. Somatic mutations were found in TP53, PTEN, IDH1, PIK3CA, EGFR, BRAF, EPHA3, NRAS, TGFBR2, FLT3 and RPS6KC1. Mapping the mutated genes into known signaling pathways revealed that the large majority of them plays a central role in the PI3K-AKT pathway.
Conclusions:
The knowledge that at least 50% of glioblastoma tumors display mutational activation of the PI3K-AKT pathway should offer new opportunities for the rational development of therapeutic approaches for glioblastomas. However, due to the development of resistance mechanisms, kinase inhibition studies targeting the PI3K-AKT pathway for relapsing glioblastoma have mostly failed thus far. Other therapies should be investigated, targeting early events in gliomagenesis that involve both kinases and non-kinases.
Insights
Glioblastoma tumors frequently show mutations in the PI3K-AKT pathway, offering new therapeutic targets. However, resistance limits kinase inhibitors, necessitating exploration of other early gliomagenesis targets.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Glioblastoma is an aggressive brain tumor with no effective cure.
- Identifying novel therapeutic targets is crucial for improving patient outcomes.
Purpose of the Study:
- To conduct a comprehensive mutation analysis of kinase genes in glioblastoma.
- To identify potential new therapeutic targets by examining genetic alterations.
Main Methods:
- Sequenced 174 exons of 39 genes in 113 glioblastoma samples and 16 high-grade glioma cell lines.
- Included known glioblastoma-associated genes (IDH1, IDH2, PTEN, TP53, NRAS) in the analysis.
- Utilized database mining and literature search to identify relevant kinase genes.
Main Results:
- Identified 148 non-synonymous somatic mutations, with 25 novel to glioblastoma.
- Found mutations in key genes including TP53, PTEN, IDH1, PIK3CA, EGFR, and BRAF.
- Overwhelmingly, mutated genes were central to the PI3K-AKT signaling pathway.
Conclusions:
- Mutational activation of the PI3K-AKT pathway occurs in over 50% of glioblastomas, presenting therapeutic opportunities.
- Resistance mechanisms have largely thwarted PI3K-AKT pathway kinase inhibitor efficacy in relapsed glioblastoma.
- Investigating therapies targeting early gliomagenesis, involving both kinases and non-kinases, is recommended.
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