Background: Alteration in metabolic activities is a critical step in cancer progression, and a myriad of metabolic-based therapy options are increasingly being proposed for human tumors. However, emerging evidence highlights interpatient metabolic heterogeneity and underscores the importance of metabolic phenotyping in cancer treatment.
Objectives: To investigate metabolic heterogeneity in cutaneous squamous cell carcinoma (cSCC), and its impact on cSCC characteristics and treatment responses.
Methods: We applied combined proteomic and bioenergetic analyses to patient samples representing various stages of cSCC, ranging from precancerous actinic keratosis (AK) to metastatic cSCC. To investigate the functional impacts of the identified metabolic heterogeneities on tumor characteristics and treatment responses, we employed patient-derived tumor cell (PDC) and patient-derived xenograft (PDX) models by transplanting tumor cells and freshly resected patient tumors into immunocompromised mice.
Results: Three subgroups with low-, medium-, and high-metabolic scores were identified across all stages of carcinogenesis. Our functional analyses indicated that, in both models (PDC and PDX), the sensitivities of tumors 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.
Conclusions: These findings demonstrate the relevance of metabolic profiling and scoring in the design of therapeutic approaches targeting the bioenergetic vulnerabilities of tumors and suggest DHODH as a promising therapeutic target in the low-metabolic score subgroup of cSCC.
© The Author(s) 2025. Published by Oxford University Press on behalf of British Association of Dermatologists.