DHODH Drives Sunitinib Resistance Via a Non-Enzymatic Mechanism by Inhibiting TRIM28 Ubiquitination and Consequent VEGFA Activation in RCC - PubMed
3 hours ago
- #renal cell carcinoma
- #DHODH
- #sunitinib resistance
- DHODH is identified as a key regulator in sunitinib resistance in renal cell carcinoma (RCC) through proteomic profiling of patient-derived xenograft models.
- DHODH competes with E3 ligase TRIM37 for binding to TRIM28, inhibiting its ubiquitination and stabilizing it, which leads to TRIM28 activating VEGFA transcription and promoting resistance.
- The small-molecule inhibitor lisaftoclax disrupts the DHODH-TRIM28 interaction, enhancing sunitinib efficacy and showing synergistic therapeutic potential in overcoming resistance.
- The study proposes DHODH as a therapeutic target and provides a novel strategy for treating sunitinib-resistant RCC, highlighting a non-enzymatic mechanism of action.