USP18 drives cisplatin resistance in ovarian cancer by modulating DNA repair, a peptide inhibitor shows promise.

Despite initial responsiveness, many patients with ovarian cancer develop resistance to platinum-based therapy, leading to high recurrence rates and poor prognosis. Current treatment strategies often fail to overcome this resistance, necessitating the identification of novel therapeutic targets. Deubiquitinases (DUBs) are proteases that regulate protein stability and function, with emerging but largely unexplored roles in cancer drug resistance. Understanding how DUBs contribute to this resistance could unlock new pathways for intervention.

Researchers conducted a CRISPR/Cas9 screen targeting the DUB family to identify genes critical for cisplatin-resistant ovarian carcinoma cell survival. They applied preclinical pharmacology approaches, RNA sequencing, proteomic analyses, computational tools, and surface plasma resonance. The study involved both cell line experiments and in vivo studies in mice. A novel peptide-based USP18 inhibitor was synthesized and tested for its ability to suppress the growth of cisplatin-resistant cells.

The CRISPR/Cas9 screen identified USP18 as a crucial survival factor in cisplatin-resistant ovarian cancer cells. USP18 expression was consistently elevated at both mRNA and protein levels across five distinct cisplatin-resistant cell variants. Genetic manipulation, including knockdown and CRISPR/Cas9 editing of USP18, significantly sensitized these cells to cisplatin, demonstrating a direct link between USP18 and drug resistance. This enhanced sensitivity coincided with impaired repair of cisplatin-induced DNA damage.

Enhanced sensitivity to cisplatin was also evident from studies in mice, confirming the in vivo relevance of USP18 inhibition. RNA-seq analysis of USP18 RNA interfered and edited cells revealed significant modulation of pathways, including those involved in DNA repair. Furthermore, a peptide-based USP18 inhibitor effectively suppressed growth of cisplatin-resistant cells, reinforcing USP18's role in sustaining their proliferation and survival.