Clinical and preclinical insights into a novel MDM2::PDGFRA fusion in recurrent glioblastoma
Abstract Glioblastoma is an aggressive and treatment-refractory primary brain tumor with limited therapeutic options and high recurrence. The molecular heterogeneity of glioblastoma poses a significant challenge to therapeutic development, as targeted therapies have mostly failed in small-scale clin...
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| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-08-01
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| Series: | npj Precision Oncology |
| Online Access: | https://doi.org/10.1038/s41698-025-01076-4 |
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| Summary: | Abstract Glioblastoma is an aggressive and treatment-refractory primary brain tumor with limited therapeutic options and high recurrence. The molecular heterogeneity of glioblastoma poses a significant challenge to therapeutic development, as targeted therapies have mostly failed in small-scale clinical trials, underscoring the need for comprehensive next-generation sequencing (NGS) characterization to identify mechanisms of resistance. In this study, we identify and functionally characterize a novel amplified fusion, MDM2 (exon 1)::PDGFRA (exon 8), mediating resistance to cetuximab in an EGFR-amplified glioblastoma. The fusion results in a truncated PDGFRA isoform, in vitro assays demonstrate that MDM2::PDGFRA acts as a constitutively active oncogenic driver with a distinct sensitivity profile to tyrosine kinase inhibitors. Analysis of a glioblastoma cohort indicates PDGFRA structural variants often co-occur with amplification and may serve as biomarkers. These findings highlight the importance of repeat NGS profiling in clinical management and provide a translational framework for identifying and targeting emergent fusion-driven alterations. |
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| ISSN: | 2397-768X |