2. Academic Validation
  3. Somatic CRISPR tumorigenesis and multiomic analysis reveal a pentose phosphate pathway disruption vulnerability in MPNSTs

Somatic CRISPR tumorigenesis and multiomic analysis reveal a pentose phosphate pathway disruption vulnerability in MPNSTs

  • Sci Adv. 2025 Aug 15;11(33):eadu2906. doi: 10.1126/sciadv.adu2906.
Gavin R McGivney 1 2 3,  Qierra R Brockman 1 2 4,  Nicholas Borcherding 5,  Amanda Scherer 1 2,  Adam J Rauckhorst 3 6 7,  Wade R Gutierrez 1 2 8,  Shane R Solst 2 9,  Collin D Heer 2 9,  Akshaya Warrier 1 2,  Warren Floyd 10,  David G Kirsch 11 12,  Vickie L Knepper-Adrian 1,  Emily A Laverty 1,  Grace A Roughton 1,  Douglas R Spitz 2 9,  Eric B Taylor 2 3 6 7 13 14,  Rebecca D Dodd 1 2
Affiliations

Affiliations

  • 1 Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA.
  • 2 Holden Comprehensive Cancer Center, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA.
  • 3 Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA.
  • 4 Department of Medicine, Anschutz Medical Campus, University of Colorado Cancer Center, Aurora, CO 80045, USA.
  • 5 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 6 Fraternal Order of Eagles Diabetes Research Center (FOEDRC), University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA.
  • 7 FOEDRC Metabolomics Core Research Facility, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA.
  • 8 Department of Urology, Mayo Clinic, Rochester, MN 55905, USA.
  • 9 Department of Radiation Oncology, Free Radical and Radiation Biology Program, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA.
  • 10 Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 11 Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network and the University of Toronto, Toronto, ON, Canada.
  • 12 Department of Radiation Oncology and Medical Biophysics, University of Toronto, Toronto, ON, Canada.
  • 13 Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA.
  • 14 Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA.
PMID: 40802750 DOI: 10.1126/sciadv.adu2906
Abstract

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive and chemo-resistant sarcomas with poor survival rates. Loss of CDKN2A or P53 following NF1 disruption is a key event in MPNST development. Here, we used CRISPR-Cas9 somatic tumorigenesis in mice to identify transcriptomic and metabolomic features distinguishing CDKN2A- versus P53-deleted MPNSTs. Convergent, multiomic analyses revealed that CDKN2A-deleted MPNSTs are especially dependent on the pentose phosphate pathway (PPP) and NADPH metabolism for growth and viability. Disruption of glucose-6-phosphate dehydrogenase (G6PD), the PPP rate-limiting enzyme, slowed CDKN2A-deleted MPNST growth and sensitized MPNSTs to standard-of-care chemotherapy. Knockdown of the redox-regulated transcription factor NRF2 slowed MPNST growth and decreased G6PD transcription. Analysis of patient MPNSTs identified a NRF2 gene signature correlating with tumor transformation. Furthermore, G6PD and NRF2 expression in PanCancer TCGA samples correlates with patient survival. This work identifies NRF2-PPP dependency as a targetable vulnerability in these difficult-to-treat MPNSTs, particularly in the NF1/CDKN2A-deleted majority.

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