Clinical and preclinical insights into a novel MDM2::PDGFRA fusion in recurrent glioblastoma

  • NPJ Precis Oncol. 2025 Aug 16;9(1):289. doi: 10.1038/s41698-025-01076-4.
Catherine Z Beach  #  1 ,  Christopher A Febres-Aldana  #  2 ,  Juan Luis Gomez Marti  3 ,  Saeed Asiry  3 ,  Tamika Wong  4 ,  John A Boockvar  4 ,  Randy S D'Amico  4 ,  Romel Somwar  5  6 ,  Monika A Davare  7 ,  Morana Vojnic  8
Affiliations
  • 1. Department of Pediatrics, Oregon Health Sciences University, Portland, OR, USA.
  • 2. Laboratory of Pathology, National Cancer Institute, National Institute of Health, Bethesda, MD, USA.
  • 3. Department of Pathology, Lenox Hill Hospital, New York, NY, USA.
  • 4. Department of Neurological Surgery, Lenox Hill Hospital, Northwell, New York, NY, USA.
  • 5. Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 6. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 7. Department of Pediatrics, Oregon Health Sciences University, Portland, OR, USA. [email protected].
  • 8. Rutgers Cancer Institute, New Brunswick, NJ, USA. [email protected].
  • # Contributed equally.
PMID: 40819143 DOI: 10.1038/s41698-025-01076-4
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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