Discovery of TBK1-Associated Oncogenic Mechanisms in Patients With Upper Tract Urothelial Carcinoma and Pre-Existing End-Stage Renal Disease.

BACKGROUND

Upper tract urothelial carcinoma is an aggressive malignancy originating from the transitional epithelium of the urinary tract. UTUC patients with pre-existing end stage renal disease (ESRD) have limited perioperative treatment options due to severely impaired bilateral kidney functions. We therefore sought to identify targetable oncogenic mechanisms in this patient population.

METHODS

A single-center retrospective study analyzed 50 fresh frozen UTUC tumor samples (17 with ESRD, 33 without) using RNA sequencing for transcriptomics profiling. Gene set enrichment analysis was performed to identify gene sets collectively enriched in ESRD tumors, with normalized enrichment score (NES) used to standardize enrichment magnitude across sets of varying sizes. Regular hemodialysis prior to UTUC diagnosis was used to identify patients with ESRD. Immunohistochemical staining was conducted on paraffin-embedded slides (6 with ESRD, 7 without) to demonstrate the involvement of representative proteins in the gene set. Candidate drugs were ranked via Connectivity Map analysis, and the drug with the highest inhibition score were further assessed through in vitro cell viability and migration assays.

RESULTS

Because overall and cancer‑specific survival did not differ significantly between groups, we interpreted transcriptomic differences as intrinsic tumor characteristics rather than consequences of disease severity. TBK1-associated gene sets were enriched in ESRD-UTUC patients (NES = 2.065, FDR q value = 0.001). Immunohistochemistry confirmed higher TBK1 levels in ESRD tissues (P = .044). A IKK/NF-κB inhibitor, Withaferin A (CAS No. 5119-48-2), emerged as a leading candidate drug (score of inhibition = 2.521). The in vitro assays demonstrated the effectiveness of Withaferin A in reducing the viability and migration of UTUC cells, suggesting potential for further clinical investigation.

CONCLUSIONS

The TBK1-associated oncogenic mechanism is prominent in UTUC patients with preexisting ESRD. Withaferin A demonstrates preclinical promise as a therapeutic candidate targeting this mechanism in UTUC patients with compromised renal function.