Predicting Poor Efficacy of Cabozantinib in Advanced Renal Cell Carcinoma by Exploratory Metabolic Pathway Analysis and In Vitro Verification.

Authors

Takanari Sakai, Yoshihide Kawasaki, Izumi Sakamoto, Eiji Hishinuma, Naomi Matsukawa, Daigo Chiba, Tomonori Sato, Kento Morozumi, Masamitsu Maekawa, Nariyasu Mano, Akihiro Ito

Published in

Cancer medicine. Volume 15. Issue 8. Pages e72145.

Abstract

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.
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.
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.
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.

PMID:
42538613
Bibliographic data and abstract were imported from PubMed on 01 Aug 2026.

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