Somatic CRISPR tumorigenesis and multiomic analysis reveal a pentose phosphate pathway disruption vulnerability in MPNSTs
- Gavin R. McGivney
- Qierra R. Brockman
- Nicholas Borcherding
- Amanda Scherer
- Adam J. Rauckhorst
- Wade R. Gutierrez
- Shane R. Solst
- Collin D. Heer
- Akshaya Warrier
- Warren Floyd
- David G. Kirsch
- Vickie L. Knepper-Adrian
- Emily A. Laverty
- Grace A. Roughton
- Douglas R. Spitz
- Eric B. Taylor
- Rebecca D. Dodd
2025-08-13
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.