Predicting Poor Efficacy of Cabozantinib in Advanced Renal Cell Carcinoma by Exploratory Metabolic Pathway Analysis and In Vitro Verification
In brief
Five-metabolite panel predicts poor cabozantinib response in advanced kidney cancer
In a retrospective series of 19 patients with clear-cell renal carcinoma, serum metabolomics identified five metabolites linked to resistance, and the same pathways were confirmed in cabozantinib-resistant cell lines. The authors propose this metabolic signature could help select patients unlikely to benefit, but validation in larger cohorts is still needed.
- Journal
- Cancer medicine (Q1)
- Published
- 1 August 2026
- Study design
- Retrospective cohort
- Evidence level
- Level 3, Low (CEBM 3b)
- Authors
- Takanari Sakai, Yoshihide Kawasaki, Izumi Sakamoto, Eiji Hishinuma, Naomi Matsukawa, Daigo Chiba, et al.
- PMID
- 42538613
- DOI
- 10.1002/cam4.72145
Why clinicians should know about it
- Picked for Biochemistry (medical) (paper of the day, 2 August 2026).
Abstract
BACKGROUND: Cabozantinib (CABO) is currently an essential drug for first-line and sequential therapy in the treatment of advanced renal cell carcinoma (RCC). Predicting its therapeutic efficacy will enable efficient drug selection and improve the prognosis of patients. We conducted an exploratory study to predict the effects of CABO using metabolite analysis with clinical and in vitro samples. METHODS: Patients diagnosed with RCC at our hospital between September 2011 and August 2023 who were pathologically diagnosed with clear cell RCC and subsequently received systemic therapy for disease progression or recurrence were included. Patient background, treatment course, and prognosis were retrospectively investigated. Patients were divided into CABO responders and poor responders based on survival analysis. Comprehensive metabolite analysis of serum samples before CABO administration was performed using a non-targeted analysis system (Orbitrap) with a mass spectrometer. The significance of metabolic pathways related to the poor response of CABO analysis was evaluated by establishing CABO-resistant renal cancer cell lines and conducting in vitro quantitative analysis. RESULTS: A total of 19 analyzable cases were identified during the study period, and seven pathways (methylhistamine metabolism, caffeine metabolism, beta-alanine metabolism, histidine metabolism, glycine and serine metabolism, tryptophan metabolism, and purine metabolism) and five metabolites (methylhistidine, kynurenic acid, xanthine, 7-methylxanthine, and L-2-amino-3-oxobutanoic acid) related to the poor efficacy of CABO were identified in a two-group comparison. Quantitative metabolite analysis of CABO-resistant cell lines established from three different renal cancer cell lines (786-O, ACHN, and Caki-1) confirmed the identified pathways and metabolites in relation to CABO resistance. CONCLUSION: We identified key metabolites and associated metabolic pathways that may serve as predictive biomarkers for suboptimal cabozantinib efficacy in patients with advanced RCC. While further validation in independent cohorts is warranted, our findings underscore the potential of metabolomic profiling to refine therapeutic selection and improve clinical outcomes.
Abstract as published, via PubMed.
For healthcare professionals. The summary is generated by AI from the published abstract, and the evidence level is assigned automatically from the study design on the Oxford CEBM hierarchy. Neither is medical advice. Read the full paper before changing practice.