(P 12) GENETIC LANDSCAPE OF MPNST DETERMINES METABOLIC STRATEGIES AND THERAPEUTIC OPPORTUNITIES FOR COPING WITH REDOX STRESS

Objective: Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are aggressive and chemo-resistant sarcomas with poor overall survival. The distinct metabolic landscape of MPNSTs represents a unique therapeutic opportunity for these devastating cancers. Loss of tumor suppressor CDKN2A is the signature event in MPNST development, occurring in over 80% of patient samples. The majority of preclinical MPNST studies have not translated well to the clinic, possibly due to the use of models that are instead driven by p53 loss. The objective of this study is to use CRISPR/Cas9 somatic tumorigenesis mouse models to identify Cdkn2a-dependent therapeutic vulnerabilities in MPNST.

Methods: We engineered CRSIPR/Cas9 tumorigenesis models to introduce somatic mutations into target tissues of adult immune-competent mice. These models use localized injection of adenovirus containing Cas9 endonuclease and guide RNAs directly into the sciatic nerve of wildtype mice. This approach allows for a highly controlled, direct comparison of different tumor genotypes in paired littermate mice without the confounding genetic events that can occur with other mouse models. Transcriptomic and metabolomic analyses examined tumors generated by deletion of Nf1/Cdkn2a or Nf1/p53. Mechanistic studies explored the role of distinct metabolic nodes in tumor growth and chemotherapy response.

Results: Using RNASeq and GC-MS / LC-MS metabolomics, we identified the pentose phosphate pathway (PPP) and regulation of NADPH metabolism as critical metabolic nodes in MPNST. Pharmacological and genetic disruption of glucose-6-phosphate dehydrogenase (G6pd), the rate-limiting step in the PPP, slowed growth of MPNST in a Cdkn2a-dependent manner. Moreover, G6pd inhibition sensitized MPNSTs to doxorubicin, a standard-of-care chemotherapy. We also identified a key role for the redox-regulated transcription factor NRF2 in MPNSTs growth, as NRF2 knockdown decreased cell viability. Genomic analysis of patient samples shows a NRF2 gene signature that correlates with decreased patient survival, further underscoring this pathway as a therapeutic target.

Conclusion: This work identifies the G6PD/NADPH axis as a central metabolic vulnerability in MPNST. Furthermore, G6PD inhibition sensitizes these tumors to conventional chemotherapy. This study provides preclinical rationale for metabolic targets that can improve chemotherapy outcomes and lower toxicities in sarcoma.