2210P - Reprogramming of pyrimidine metabolism drives tumorigenesis in NF2-deficient malignant pleural mesothelioma

Background

Malignant pleural mesothelioma (MPM) is a highly aggressive cancer, notoriously known because of limited treatment options and a dismal prognosis. MPM features a difficult-to-target genome dominated by widespread loss of function mutations in tumor suppressor genes (TSGs), among which neurofibromin 2 (NF2) is one of the most altered TSGs and accounts for around 40-50% of MPM patients. Despite extensive and continuous efforts, the underlying pathobiology of NF2-related tumorigenesis remains obscure. In particular, targeted therapies, a mainstay in the clinical management of many other tumors, have not emerged in MPM.

Methods

In this study, we have taken a genome-wide CRISPR/Cas9 knockout screening to identify therapeutically relevant genetic vulnerabilities in NF2-deficient MPM cells. Further, integrated analysis of multiple-omics data (transcriptome, proteome, and metabolome) based on the gene-edited cell models and patients’ tumor samples was implemented to systematically decipher the molecular basis underlying NF2-facilitated tumorigenesis. Subsequently, in vitro and in vivo preclinical orthotopic mouse models were performed to delineate the genetic dependency of NF2-deficient MPM cells.

Results

Here, we show that NF2-deficient MPM cells display a preferential sensitivity towards the disruption of genes involved in de novo pyrimidine metabolism, including CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotase) and DHODH (dihydroorotate dehydrogenase). Further exploration uncovers that the adaptive reprogramming of the de novo pyrimidine synthesis pathway is a critical molecular alteration in the NF2-deficient MPM. In addition, we observe that the constitutive activation of YAP1(Yes-associated protein 1) in NF2-deficient MPM triggers the boosted transcription of rate-limiting enzymes in the de novo pyrimidine synthesis. Coherently, pharmacological inhibition of DHODH exerted a more potent anti-tumor effect in an orthotopic mouse model of MPM.

Conclusions

Taken together, our work delineates the molecular basis and metabolic vulnerability driven by NF2 inactivation while also providing a novel therapeutic target to battle against this daunting disease.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Y. Shu.

Funding

Postdoctoral Science Foundation of China.

Disclosure

All authors have declared no conflicts of interest.