Citations 1
Somatic CRISPR tumorigenesis and multiomic analysis reveal a pentose phosphate pathway disruption vulnerability in MPNSTs
McGivney, Gavin R. , Brockman, Qierra R. , Borcherding, Nicholas , Scherer, Amanda , Rauckhorst, Adam J. , Gutierrez, Wade R. , Solst, Shane R. , Heer, Collin D. , Warrier, Akshaya , Floyd, Warren , Kirsch, David G. , Knepper-Adrian, Vickie, Laverty, Emily A. , Roughton, Grace A. , Spitz, Douglas R. , Taylor, Eric B. , Dodd, Rebecca D. , Knepper-Adrian, Vickie L , Borcherding, Nicholas , Spitz, Douglas R
Science Advances | August 13, 2025 | Volume: 11 | Issue: 33 | Pages: No page available
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.