Poster Presentation 47th Lorne Genome Conference 2026

Genome-wide CRISPR-KO library screen reveals ribosome biogenesis as a genetic vulnerability in ARID1A-mutant ovarian clear cell carcinoma. (133273)

Tali S Skipper 1 , Kristie-Ann Dickson 1 , Tian Y Du 2 , Matthew A Waller 2 , Christopher E Denes 2 , Nikola A Bowden 3 , Alen Faiz 4 , Greg G Neely 2 , Deborah J Marsh 1
  1. Translational Oncology Group, School of Life Science, Faculty of Science, University of Technology Sydney, Ultimo, NSW, Australia
  2. Dr. John and Anne Chong Lab for Functional Genomics, Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Camperdown, NSW, Australia
  3. School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia
  4. Respiratory Bioinformatics and Molecular Biology Group, School of Life Sciences, , Faculty of Science, University of Technology Sydney, Ultimo, NSW, Australia

Genome-wide CRISPR-KO library screens provide a platform for identifying synthetic lethal combinations that may be leveraged for new precision medicine approaches, particularly in diseases with limited therapeutic options. Mutations in ARID1A, a gene that, together with ARID1B, encodes one of two mutually exclusive DNA binding subunits of the SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatin remodelling complex, are present in 6‑10% of all human malignancies. This presents a therapeutic vulnerability, whereby harnessing ARID1A synthetic lethal interactions could serve as a strategy for selectively killing cancer cells.

Somatic ARID1A mutations are present in up to two thirds of a rare epithelial ovarian cancer subtype, ovarian clear cell carcinoma (OCCC). Current first-line treatment involves surgical debulking and platinum- and taxol-based chemotherapy; however, this is only successful in 11‑27% of cases and is mostly ineffective at treating recurrent disease. Consequently, new treatments are urgently needed. ARID1B is a known ARID1A synthetic lethal partner and is recognised as a target for ARID1A mutant malignancy, however, treatments exploiting this relationship are yet to be revealed. To uncover new synthetic lethal strategies for targeting ARID1A mutant OCCC, we screened a CRISPR-Cas9 engineered ARID1A-KO isogenic cell line panel, derived from the OCCC cell line RMG-1, using the TKOv3 (Toronto Knockout version 3) CRISPR library.

Canonical pathway enrichment analysis of genes uniquely negatively selected in ARID1A-KO cells highlighted an enrichment of pathways connected with ribosome biogenesis; namely, rRNA processing in the nucleolus and cytosol, eukaryotic translation initiation, ribosomal quality control signalling, and eukaryotic translation termination. This suggests that disruptions to ribosome assembly and function may represent a key genetic vulnerability in ARID1A mutant cells. Targeting ribosome biogenesis, for example with RNA polymerase Ι inhibitors, could therefore offer new strategies for treating ARID1A mutant OCCC.