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

2025/08/13 by Gavin R. McGivney, Qierra R. Brockman, Nicholas Borcherding +14 · 1 voice
Biochemistry, Genetics and Molecular Biology · Medicine · #Autophagy in Disease and Therapy #CRISPR and Genetic Engineering #RNA modifications and cancer

paper · pdf · doi:10.1126/sciadv.adu2906

openalex publication_date 2025/08/13 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/27

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.

Citations

• Upgrade of an old drug: Auranofin in innovative cancer therapies to overcome drug resistance and to increase drug effectiveness

Discussions

• Congratulations to Dr. Eric Taylor, his lab, and collaborators on their new publication “Somatic CRISPR tumorigenesis and multiomic analysis reveal a pentose phosphate pathway disruption vulnerability [bsky, 2 points, 0 comments]

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