靶向基底样乳腺癌的代谢脆弱性

Triple Negative Breast Cancers (TNBC) are a biologically heterogeneous clinical subtype of breast cancer with limited treatment options and generally poor prognosis. Basal-like breast cancer (BLBC), which accounts for ~75% of TNBCs by gene expression profiling, is particularly aggressive, highlighting an urgent need to develop targeted therapies for this subtype. Our lab previously identified an enrichment of pyrimidine synthesis metabolites in tumors from BLBC patients. Further, an analysis of the Chinese Breast Cancer Genome Atlas (PMID: 38347143), a multi-omics dataset including 443 breast cancer metabolomics samples, also revealed a similar feature of pyrimidine-enriched metabolites in both BLBC and TNBC tumors. Therefore, we hypothesize that pyrimidine biosynthesis is essential for BLBC survival and may represent a therapeutic vulnerability. To investigate this unique metabolic phenotype, we utilized a panel of syngeneic, serially transplanted, genetically engineered mouse (GEM) model mammary tumors representing multiple breast cancer subtypes (luminal, basal-like, mesenchymal). Metabolomic mass spectrometry of 20 GEM models, including 6 BLBC models and normal mammary glands, identified 2 distinct metabolic subtypes, namely a Nucleotide-enriched and Fatty Acid-enriched groups, mirroring the patterns observed in human breast tumors. To evaluate the dependency of these murine tumors on pyrimidine biosynthesis, we used leflunomide, an FDA-approved dihydroorotate dehydrogenase (DHODH) inhibitor. In vivo testing across 4 tumor models, including the basal-like p53-null 2225L model, showed that leflunomide slowed tumor growth and extended survival in 3 models. However, 1 model exhibited resistance, suggesting that combination therapies may still be needed. To identify potential combination therapies based upon DHODH inhibitors, we conducted a drug combination screen using both the murine 2225L and human SUM102 basal-like cell lines. Notably, we found that kinase inhibitors with off-target activity against ENT1 sensitized cells to DHODH inhibition. These findings are currently being validated in vivo , which may support a strategy of co-targeting pyrimidine biosynthesis and the nucleotide salvage pathways to overcome resistance.