Poster Presentation 35th Lorne Cancer Conference 2023

Activation of nucleolar DNA damage response as a therapeutic strategy for ovarian cancer (#359)

Jiachen Xuan 1 2 , Keefe Chan 1 , Natalie Brajanovski 1 , Henry Beetham 1 3 , Kaylene Simpson 1 4 , Clare Scott 5 , Rick Pearson 1 , Elaine Sanij 1 2
  1. Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  2. St Vincent's Institute of Medical Research, Fitzroy
  3. Victorian Centre for Functional Genomic , Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  4. Victoria Centre for Functional Genomc, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  5. Walter and Eliza Hall Institute, Melbourne, VIC, Australia

High-grade serous ovarian cancer (HGSOC) accounts for 70-80% of ovarian cancer deaths. Approximately 50% of HGSOC have defects in the homologous recombination (HR) DNA repair pathway more frequently BRCA1/2. HR-deficient tumours are sensitive to chemotherapy and PARP inhibitors (PARPi). However, tumours frequently acquire resistance to therapy emphasising the need for new therapies.

Our laboratory developed the “first in class” novel small molecule inhibitor of RNA polymerase I transcription of ribosomal RNA (rRNA) genes, CX-5461 that selectively kills cancer cells and is currently in phase I clinical trials in haematologic and breast cancers(1).

Importantly, our lab has demonstrated that CX-5461 exhibits significant single-agent efficacy in PARPi-sensitive and PARPi-resistant HGSOC-PDXs in vivo(2). In this project, we have investigated the molecular and cellular response to CX-5461. We have shown that CX-5461 has significant anti-growth effects across a panel of HGSOC cell lines, characterized with respect to their sensitivity to cisplatin and PARPi and HR status. We have also demonstrated that CX-5461 is synthetic lethal with HR-deficiency in HGSOC due to enhanced replication stress associated with replication fork stalling and degradation. Furthermore, we have shown that CX-5461 induces DNA damage response (DDR) specific to nucleolus in HGSOC cells, leading to global DDR with low levels of DNA damage. To further investigate the synthetic lethal interactions with CX-5461, we performed a boutique CRISPR-Cas9 library of DDR genes and identified that CX-5461 has a strong and unique interaction with DNA repair pathways in inhibiting OVCAR8 cell growth.  Our data show that deletion of specific DNA repair genes exacerbates CX-5461-nucleolar stress response and growth arrest phenotypes.

Altogether, our work highlights harnessing nucleolar stress and DDR as an exciting approach that can induce replication stress to inhibit proliferation without the collateral DNA damage associated with chemotherapy. We propose that mediators of nucleolar stress that destabilise replication forks represent attractive novel cancer therapeutic targets in chemo-resistant ovarian cancer.

  1. Khot, A., et al. (2019). "First-in-Human RNA Polymerase I Transcription Inhibitor CX-5461 in Patients with Advanced Hematologic Cancers: Results of a Phase I Dose-Escalation Study." Cancer Discov 9(8): 1036-1049.
  2. Sanij, E., et al. (2020). "CX-5461 activates the DNA damage response and demonstrates therapeutic efficacy in high-grade serous ovarian cancer." Nature Communications 11(1)