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
  • 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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