Clinical and preclinical insights into a novel MDM2::PDGFRA fusion in recurrent glioblastoma Journal Article
| Authors: | Beach, C. Z.; Febres-Aldana, C. A.; Martí, J. L. G.; Asiry, S.; Wong, T.; Boockvar, J. A.; D'Amico, R. S.; Somwar, R.; Davare, M. A.; Vojnic, M. |
| Article Title: | 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 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. © 2025 Elsevier B.V., All rights reserved. |
| Journal Title: | npj Precision Oncology |
| Volume: | 9 |
| Issue: | 1 |
| ISSN: | 2397768X |
| Publisher: | Elsevier B.V. |
| Date Published: | 2025-01-01 |
| Start Page: | 289 |
| Language: | English |
| DOI: | 10.1038/s41698-025-01076-4 |
| PROVIDER: | scopus |
| PMCID: | PMC12357959 |
| PUBMED: | 40819143 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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