High-grade serous ovarian cancer (HGSOC) is characterised by frequent alterations of genes involved in the homologous recombination (HR) DNA repair pathway, most frequently BRCA1/21. HR deficient tumours are sensitive to platinum-based chemotherapy and Poly-(ADP-ribose) polymerase (PARP) inhibitors (PARPi). On this basis, the PARPi olaparib has been approved as a maintenance monotherapy in advanced ovarian cancer patients with germline BRCA mutations following complete or partial response to platinum-based chemotherapy. However, clinical resistance to PARPi and platinum-based therapies is associated with complex mechanisms including acquired HR proficiency and stabilisation of DNA replication forks. Thus, novel therapeutic strategies that circumvent PARPi-resistance will provide a major advance in ovarian cancer therapy.
The novel small molecule inhibitor of RNA polymerase I (Pol I) transcription of ribosomal RNA genes CX-54612-5 has shown selective toxicity against BRCA1/2 deficiencies in solid cancer cell lines6 and is currently in phase I clinical trials in haematologic (Peter Mac) and solid cancers (Canada Cancer Trials Group). Here, we demonstrate that CX-5461 exhibits synthetic lethality with HR deficiency in HGSOC cells and has significant therapeutic benefit in HR-deficient HGSOC patient-derived xenograft (PDX) in vivo.
Further, we have demonstrated that CX-5461 activates a DNA damage response (DDR) at rRNA genes leading to MRE11 nuclease-dependent degradation of DNA replication forks. CX-5461 mediated effects on fork destabilisation are distinct from PARPi. Importantly, we demonstrate CX-5461 cooperates with PARPi in exacerbating DNA damage to prolong survival in a HR-deficient HGSOC-patient-derived xenograft (PDX). Further, CX-5461 exhibits significant efficacy in PARPi-resistant HGSOC-PDX. Furthermore, we have identified CX-5461-sensitivity gene expression signatures in primary and relapsed HGSOC, highlighting the potential of CX-5461 as an exciting promising therapy against relapsed HGSOC and in combination therapy with PARPi to significantly delay resistance.