Background: 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.
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 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.
Results: 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.
Conclusions: 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.
Cutaneous squamous cell carcinoma (cSCC) is the second most common type of skin cancer. The number of cases is rising due to ageing populations and exposure to UV light. Most patients with cSCC have a good outcome. But, aggressive forms of cSCC can lead to poor outcomes and even death. We need new treatments and ways to find patients with cSCC who may respond well to specific therapy. Cancer cell metabolism is the way in which tumour cells generate energy. This plays a crucial role in how cancer cells behave and respond to treatment. In this study, we created a metabolic scoring system to classify cSCC tumours. We investigated how these scores relate to tumour characteristics and treatment responses. Using cSCC samples and comparing them to healthy skin, we found three cSCC subgroups. These subgroups had low, medium and high metabolic scores. cSCC tumours with low metabolic scores responded better to a drug called ‘leflunomide’. Leflunomide targets a key enzyme in metabolism called ‘dihydroorotate dehydrogenase’ (DHODH). cSCC tumours became sensitive to leflunomide when the levels of DHODH were higher. A metabolic scoring system could help personalize treatment for patients with cSCC. It may help find people who respond well to treatments targeting tumour metabolism. Treatments that target DHODH are promising in cSCC tumours with low metabolic scores.
© The Author(s) 2025. Published by Oxford University Press on behalf of British Association of Dermatologists.