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<p>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, <i>MDM2</i> (exon 1)::<i>PDGFRA</i> (exon 8), mediating resistance to cetuximab in an <i>EGFR</i>-amplified glioblastoma. The fusion results in a truncated PDGFRA isoform, in vitro assays demonstrate that <i>MDM2::PDGFRA</i> acts as a constitutively active oncogenic driver with a distinct sensitivity profile to tyrosine kinase inhibitors. Analysis of a glioblastoma cohort indicates <i>PDGFRA</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月16日

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  • Catherine Z. Beach,
  • Christopher A. Febres-Aldana,
  • Juan Luis Gomez Marti,
  • Saeed Asiry,
  • Tamika Wong,
  • John A. Boockvar,
  • Randy S. D’Amico,
  • Romel Somwar,
  • Monika A. Davare,
  • Morana Vojnic

摘要

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.