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. While HR-deficient tumours are initially sensitive to chemotherapy and PARP inhibitors (PARPi), the development of acquired resistance is common emphasising the need for novel therapies.
The “first in class” drug CX-5461 inhibits RNA polymerase I (Pol I) transcription of ribosomal RNA genes has shown promising clinical activity in Phase I clinical trials in patients with haematologic (Peter Mac)(1) and breast cancers (Canada).
Our lab has demonstrated that CX-5461 exhibits significant single-agent efficacy in PARPi-sensitive and PARPi-resistant HGSOC-PDXs in vivo (2). Our data demonstrate CX-5461 exhibits a different spectrum of cytotoxicity to PARPi and chemotherapy due to its distinct mode of action in inducing DNA damage response (DDR). CX-5461 activates the DDR at the rRNA genes within the nucleoli leading to global replication stress involving degradation of DNA replication forks. Importantly, CX-5461 exhibits efficacy in patient-derived HGSOC cells with reduced sensitivity to PARPi involving stabilisation of stalled replication forks, a common mechanism of resistance to chemotherapy and PARPi. CX-5461 also co-operates with PARPi in exacerbating replication stress via increasing replication stress and enhances therapeutic efficacy against BRCA2-mutated HGSOC-PDX in vivo. We propose CX-5461 is a promising therapy in combination with PARPi for the treatment of HGSOC including relapsed disease.
Further, our recent work has demonstrated that CX-5461 exhibits powerful synthetic lethal interactions with various DNA repair pathways revealing the power of activating nucleolar DDR in cancer therapy (3). Our current work utilises CRISPR-CAS9 screening approaches to characterise nucleolar DDR and how it mediates replication stress and to understand the mechanisms underlying CX-5461’s cooperation with PARPi in inhibiting the growth of HGSOC cells. This work will provide evidence for the potential of CX-5461 alone and in combination therapy approaches against HGSOC and for initiating clinical trials to improve patients’ outcomes.