Abstract

Targeted therapy for advanced colorectal cancer (CRC) remains a significant unmet clinical need. Here, we investigate the mechanism of the anti-TROP2 antibody-drug conjugate IMMU132, delivering SN-38 to induce TOP1-mediated DNA damage and cytotoxicity. We further discover that it concurrently suppresses the PERK-eIF2α-ATF4 axis of the unfolded protein response, a key adaptive survival pathway activated by therapy-induced endoplasmic reticulum (ER) stress. This dual action of direct killing and stress adaptation disruption may dismantle a key resistance mechanism. Furthermore, combining IMMU132 with the PERK inhibitor GSK2606414 yields potent synergy across various CRC preclinical models. Mechanistically, this synergy stems from the enhanced suppression of ER stress and the oncogenic Wnt/β-catenin pathway. Thus, our findings reveal that co-targeting the DNA damage response, the PERK pathway, and the Wnt/β-catenin pathway is a promising strategy to overcome resistance to TROP2-directed antibody-drug conjugates (ADCs) in advanced CRC, providing a rational framework for combination therapies.