Metabolism-based scoring of cutaneous squamous cell carcinoma to predict tumour features and responses to treatment with dihydroorotate dehydrogenase inhibitors.

Abstract

Alteration in metabolic activities is a critical step in cancer progression. Myriad metabolic-based therapy options are increasingly being proposed for human tumours. However, emerging evidence highlights interpatient metabolic heterogeneity and underscores the importance of metabolic phenotyping in cancer treatment. To investigate metabolic heterogeneity in cutaneous squamous cell carcinoma (cSCC) and its impact on cSCC characteristics and treatment responses. We applied combined proteomic and bioenergetic analyses to patient samples representing various stages of cSCC, ranging from precancerous actinic keratosis to metastatic cSCC. To investigate the functional impacts of the identified metabolic heterogeneities on tumour characteristics and treatment responses, we used patient-derived tumour cell (PDC) and patient-derived xenograft (PDX) models by transplanting tumour cells and freshly resected patient tumours into immunocompromised mice. Three subgroups with low, medium and high metabolic scores, respectively, were identified across all stages of carcinogenesis. Functional analyses indicated that, in both models (PDC and PDX), the sensitivities of tumours to leflunomide, an inhibitor of dihydroorotate dehydrogenase (DHODH), were inversely correlated with their metabolic scores and directly correlated with DHODH protein expression level. Moreover, DHODH overexpression in nonresponding groups rendered them sensitive to leflunomide. The findings demonstrate the relevance of metabolic profiling and scoring in the design of therapeutic approaches targeting the bioenergetic vulnerabilities of tumours and suggest DHODH as a promising therapeutic target in the low metabolic score subgroup of cSCC.