Dual Targeting of IDH2 and the Ubiquitin-Proteasome System Reveals a Functional Vulnerability in Breast Cancer Models.

ABSTRACT: Background/Objectives: Breast cancer cells rely on both mitochondrial metabolism and proteostatic mechanisms for cell fitness. The mitochondrial enzyme IDH2 supports redox balance and biosynthesis, while the ubiquitin-proteasome system (UPS) preserves protein quality. This study aimed to determine whether inhibiting IDH2 enhances sensitivity to proteasome-targeting agents across breast cancer subtypes. Methods: A panel of human and murine breast cancer cell lines was treated with the IDH2 inhibitor AGI-6780, alone or in combination with the proteasome inhibitor carfilzomib (CFZ) or the E1 ubiquitin-activating enzyme inhibitor TAK-243. Synergy was evaluated using Bliss scoring. Apoptosis, clonogenicity, and pathway modulation were assessed through Western blotting, colony-form

SUBMITTER: Gharari N 

PROVIDER: S-EPMC12896526 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature