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

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.