Ciblage thérapeutique de la vulnérabilité métabolique des carcinomes épidermoïdes cutanés

Alteration in metabolic activities is a critical step in cancer progression, and several metabolic-based therapy options areincreasingly being proposed for human tumors. However, emerging evidence highlights interpatient metabolicheterogeneity and underscores the importance of metabolic phenotyping in cancer treatment.In this study, we profiled the metabolism of human cSCC samples across stages of carcinogenesis and identified threesubgroups with low, medium, and high metabolic scores—even at the precancerous stage. We then investigate the impactof this metabolic heterogeneity on cSCC responses to inhibitors of dihydroorotate dehydrogenase (DHODH), a key enzymein de novo pyrimidine biosynthesis. Using patient-derived xenograft (PDX) models, we showed that DHODH inhibitorefficacy correlates with metabolic score, highlighting its potential for predicting treatment response. To further assess thetherapeutic potential of DHODH inhibition, we evaluated the efficacy of two DHODH inhibitors, leflunomide and PTC299,in immunocompromised mice xenografted with A431 and SCC13 cell lines. Our results demonstrate that leflunomidesignificantly inhibited tumor growth only in the A431-derived xenografts, whereas PTC299 suppressed tumor growth inboth SCC13 and A431 models.These findings highlight the relevance of metabolic profiling in the design of therapeutic strategies that target thebioenergetic vulnerabilities of tumors. They also suggest that DHODH may be a promising therapeutic target, at least in asubset of cSCC. Moreover, our data suggest that PTC299 could offer broader therapeutic benefits by potentially overcomingresistance mechanisms associated with metabolic plasticity.