These results indicate that GBM growth responses to targeted therapies previously tested in clinical trials are strongly influenced by the balance of EGFR and PDGFRA activation in individual cells, which is heterogeneous at baseline.
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.
Intratumoral heterogeneity of receptor tyrosine kinases EGFR and PDGFRA amplification in glioblastoma defines subpopulations with distinct growth factor response.
Through double-immunohistochemical staining for platelet-derived growth factor receptor α (PDGFRα) and glial fibrillary acidic protein (GFAP), this study explored the intercase variability among 45 human GBM samples regarding density of GFAP+ peritumoral astrocytes and a subset of GFAP+ peritumoral astrocyte-like cells also expressing PDGFRα.
Phosphorylated receptor tyrosine kinase profiling showed a specific activation of platelet-derived growth factor receptor alpha/beta in EGFRvIII-transduced pediatric glioblastoma cells, and targeted coinhibition with erlotinib and imatinib leads to enhanced efficacy in this model.
Genomic mapping has driven the classification of glioblastoma into distinct molecular subclasses, but mechanisms that regulate tumor subclass phenotypes are only now emerging.In this issue of Cancer Cell, Lu et al. describe a phenotypic switch from PDGFRA-enriched "proneural" to EGFR-enriched "classical" features in glioblastoma upon ablation of Olig2.
We showed that machine-based classification of GBMs with high oligodendroglioma component uncovered a set of tumors with strong associations with PDGFRA amplification, proneural transcriptional class, and expression of the oligodendrocyte signature genes MBP, HOXD1, PLP1, MOBP and PDGFRA.
The extrachromosomal nature of ALEMs explains the observed drastic changes in the amounts of mutated oncogenes (like EGFR or PDGFRA) in glioblastoma in response to environmental changes.
Tumor types were characterized by specific broad and focal chromosomal events including focal loss of the INK4A/B locus in glioblastoma and loss of the RB1 gene and amplification of the PDGFRA gene in oligodendrogliomas.
Surprisingly, we observed the induction of anti-apoptotic proteins and compensatory oncogenic signals such as EDN1, EDNRB, PRKCB1, PDGF-C and PDGF-D. To conclude, we hypothesize that the newly discovered PDGFRα/Stat3/Rb1 regulatory axis might represent a potential therapeutic target for GBM treatment.
We also detected amplifications of epidermal growth factor receptor (EGFR) or platelet-derived growth factor receptor alpha (PDGFRalpha) in a few of the 13 cases of glioblastoma multiforme analyzed.
No significant difference was observed in the frequency of amplification of these genes in primary and secondary glioblastomas or in glioblastomas with and without IDH1 mutations, suggesting that amplification of PDGFRA, KIT and KDR may be implicated in the pathogenesis of a small fraction of both subtypes of glioblastoma.
We found that PDGFRα is expressed only in a subset of GBMs, while PDGFRβ is more commonly expressed in tumors but is preferentially expressed by self-renewing tumorigenic GBM stem cells (GSCs).
Increased PDGFR-alpha mRNA expression was observed in astrocytic tumors of all stages of malignancy, although the highest levels were found in glioblastoma multiforme.
A common theme in glioblastoma is the amplification of genes that code for growth factor receptors of the protein-tyrosine kinase family (epidermal growth factor receptor, platelet-derived growth factor receptor-alpha, met).
PDGFRA amplification was more common in cases with GBM than with PNET morphology (36 vs. 5 %, respectively), while CCND2 amplifications showed the opposite trend (5 vs. 27 %).