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.

Notably, treatment with the PERK inhibitor GSK2606414 successfully reversed the UFL1 deficiency-induced upregulation of p-PERK, p-eIF2α, ATF4, and CHOP and rescued the apoptotic phenotype. Our study demonstrates for the first time that UFL1 is a critical regulator for maintaining myoblast survival and normal myofiber development, acting partly through suppressing the PERK-mediated ER sress. These findings provide novel insights into the pathogenesis of muscle developmental disorders and suggest UFL1 as a potential therapeutic target.

These findings underscore the promise of GSK2606414 and cisplatin co-treatment as a potent strategy to counteract ovarian cancer resistance. This combination could potentially advance therapeutic outcomes and provide a new pharmacological approach to resistant cancers.

P1, N=5, Terminated, Nerviano Medical Sciences | N=65 --> 5 | Trial completion date: Apr 2025 --> Jan 2024 | Recruiting --> Terminated; The decision is not based on emerging safety or efficacy concerns but on strategic reasons related to the changing and competitive treatment options in Multiple Myeloma

After inhibiting CSE activity with DL-propargylglycine (PPG i.p.), the renal tissue pathology in LPS-induced AKI mice was further exacerbated, leading to enhanced activation of the PERK/Bax-Bcl2 pathway. Our findings suggest that endogenous H2S influences the pathogenesis of SAKI, while exogenous H2S protects against LPS-induced AKI by inhibiting the PERK/Bax-Bcl2 pathway involved in ERS.

P1, N=124, Recruiting, Nerviano Medical Sciences | Not yet recruiting --> Recruiting

P1, N=124, Not yet recruiting, Nerviano Medical Sciences

We demonstrate that PERK mediated UPR regulates senescence reversal and its inhibition can be exploited as potential seno-therapeutic option in glioblastoma.

The chemicals identified as degradation enhancers include inhibitors of cellular signaling pathways such as poly-ADP ribosylation (PARG inhibitor PDD00017273), unfolded protein response (PERK inhibitor GSK2606414), and protein stabilization (HSP90 inhibitor luminespib). Consequently, these signal inhibitors sensitize cells to the PROTAC-induced apoptosis. These results suggest that various cell-intrinsic signaling pathways spontaneously counteract chemically induced target degradation at multiple steps, which could be liberated by specific inhibitors.

Importantly, treatment with the inhibitor did not affect substantially normal HPF cells at any used concentration. The results indicate that PERK inhibitors could potentially be applied as a targeted therapy for NSCLC.

P1, N=23, Completed, HiberCell, Inc. | Recruiting --> Completed | Phase classification: P1a --> P1 | N=36 --> 23

P1, N=65, Recruiting, Nerviano Medical Sciences | Trial primary completion date: Nov 2023 --> Jun 2024