USP18 impacts on platinum-resistance in ovarian cancer cells by modulating DNA repair

Aims: Deubiquitinases (DUBs) are proteases with emerging roles in cancer progression and therapy resistance, yet their contribution to drug resistance in ovarian cancer remains underexplored. Ovarian cancer patients often fail to benefit from platinum-based therapy, highlighting the need to identify novel factors involved in drug resistance. To this end we performed a CRISPR/Cas9 screen targeting DUB family to identify genes essential for platinum- resistant ovarian carcinoma cell survival. Methods: A CRISPR/CAS9 DUB knockout screen was performed on IGROV-1 parental and platinum-resistant ovarian carcinoma cells. Preclinical pharmacology approaches were also applied. Results: We identified USP18 as a survival factor in platinum-resistant ovarian cancer cells. USP18 expression was elevated at the mRNA and protein levels across five platinum-resistant cell lines. Knockdown and CRISPR/CAS9 editing of USP18 sensitized cells to cisplatin, coinciding with impaired repair of cisplatin-induced DNA damage. RNA-seq of USP18 RNA interfered and edited cells revealed the modulation of pathways including DNA repair. A peptide-based USP18 inhibitor suppressed growth of resistant cells, supporting its role in sustaining the growth of platinum-resistant cells. Conclusion: We identified USP18 as a novel mediator of platinum resistance in ovarian cancer, through modulating DNA repair. Targeting USP18 may offer a therapeutic strategy to improve outcomes in platinum-resistant ovarian cancer.