Correspondingly, a higher sensitivity to SRA737 was observed in a docetaxel-resistant CRPC cell line with elevated KDM5D, and silencing KDM5D caused resistance to this inhibitor. SIGNIFICANCE STATEMENT: This study demonstrated an important role of an epigenetic regulator KDM5D in regulating CHK1 inhibitor sensitivity via a p38/COX-2-mediated prosurvival pathway in certain castration- or drug-resistant PC cells. Our results indicate that PC cells expressing KDM5D may be more sensitive to targeted inhibition of CHK1 kinase, highlighting the potential predictive value of this gene for CHK1-targeted therapies in PC.

Dual targeting of CHK1 and PD-L1 may improve OC treatment by simultaneously suppressing stemness and enhancing anti-tumor immunity.

PROTAC MA203 contains the type I kinase inhibitor rabusertib, which preferentially inhibits activated CHK1, and the cereblon (CRBN) ligand pomalidomide. Genetic CHK1 elimination confirms that such newly recognized functions of CHK1 rely on functions beyond its well-known catalytic activity. Thus, kinase-independent functions of CHK1 can be exploited with innovative pharmacological agents.

FSTL3 overexpression completely abrogated tumor response to PPC treatment (Prexasertib combined with PD-1 and CTLA-4 blockade) compared to controls, suggesting that FSTL3 may be involved in immunotherapy resistance. In conclusion, this study suggests a role for FSTL3 as a prognostic marker and as therapeutic target in HGSOC, where it may play a role in promoting a mesenchymal tumor phenotype, maintaining an immunosuppressive tumor microenvironment, and driving immunotherapy resistance.

Furthermore, combining Prexasertib with 5-fluorouracil, a standard chemotherapeutic agent, produced a synergistic killing effect. These findings establish a novel synthetic lethal relationship between FBXO7 and CHEK1, suggesting that CHEK1 inhibition may provide a targeted therapeutic strategy for CRC patients with FBXO7 deficiencies, and highlighting the broader potential of exploiting SCF complex alterations in CRC therapy.

Cardiomyocyte CHK1 S280 phosphorylation is a key step in angiotensin II-induced cardiac remodelling, through activation of the JAK1-STAT3 pathway. Pharmacological inhibition of CHK1 could be a potential therapeutic strategy for hypertensive heart failure.

P2, N=14, Completed, Memorial Sloan Kettering Cancer Center | Recruiting --> Completed | N=24 --> 14 | Trial completion date: Mar 2026 --> Aug 2025 | Trial primary completion date: Mar 2026 --> Aug 2025

P1, N=32, Recruiting, PharmaEngine | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Dec 2025 --> Dec 2026

Strikingly, three HRP subtypes emerged, marked by unique structural alterations and gene expression patterns, tumor microenvironment interactions, and different chemotherapy responses. Finally, organoid experiments showed subtype-specific sensitivity to CHK1 inhibition, suggesting prexasertib as a potential targeted treatment for most currently untreatable HRP patients.

P1, N=127, Recruiting, Boundless Bio | Trial completion date: Sep 2027 --> Mar 2027

P2, N=353, Recruiting, Acrivon Therapeutics | Phase classification: P1/2 --> P2 | Trial completion date: Dec 2027 --> Apr 2027 | Trial primary completion date: Jul 2026 --> Oct 2026

Moreover, the specific Chk1 inhibitor rabusertib (LY2603618) significantly enhanced the efficacy of doxorubicin in both ER+ and ER- cell lines. In summary, we have identified the association of a specific miRNA profile with highly proliferative luminal BCs and demonstrated the ability of hsa-miR-195-5p to inhibit CHEK1 expression in BC in vitro, underlining the importance of CHEK1 expression and its inhibition for prognosis and treatment of patients with luminal BCs.