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Direct comparison of Cdkn2a and p53 loss reveals global transcriptomic differences, including tumor suppressor dependency on pentose phosphate pathway in MPNST

ABSTRACT: Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are aggressive and chemo-resistant sarcomas with poor overall survival. Loss of tumor suppressors CDKN2A (~80%) or P53 (~20%) is a signature event in MPNST development. Here, we use CRISPR/Cas9 somatic tumorigenesis mouse models to mechanistically compare CDKN2A and P53 loss transcriptomic and metabolic differences, leading to therapeutic vulnerabilities in MPNSTs. Multi-omic analyses identified the pentose phosphate pathway (PPP) and regulation of NADPH metabolism as critical metabolic vulnerabilities in the CDKN2A-deleted MPNSTs. Disruption of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting step in the PPP, slowed CDKN2A-deleted MPNST growth, yet sensitized both genotypes of MPNSTs to standard-of-care chemotherapy. Moreover, the redox-regulated transcription factor NRF2 controlled G6PD activity in these tumors. Genomic analysis of patient samples showed a NRF2 gene signature that correlated with tumor transformation, further underscoring this pathway as a therapeutic target. This work identifies the G6PD/NADPH axis as a central metabolic vulnerability in MPNSTs.

ORGANISM(S): Mus musculus

PROVIDER: GSE275277 | GEO | 2025/08/01

REPOSITORIES: GEO

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