High-grade serous ovarian cancer (HGSOC) accounts for 70-80% of ovarian cancer deaths. HGSOC is characterized by genomic scarring with relatively few driving oncogenes that can be therapeutically targeted. Approximaely 50% of HGSOC have defects in the homologous recombination (HR) DNA repair pathway more frequently BRCA1/2. HR-deficient tumours are senstive to chemotherapy and inhibition of additional DNA repair pathways, such as PARP inhibitors (PARPi). However, tumours frequently aquire resistance to therapy emphasising the need for novel combination therapies.
Our laboratory developed the “first in class” novel small molecule inhibitor of RNA polyemrase I transcription of ribosomal RNA genes, CX-5461 that selectively kills cancer cells and is currently in phase I/II clinical trials in haematologic (Peter Mac) and breast cancers (Canada).
Importantly, our lab has demonstrate that CX-5461 exhibits significant single agent efficacy in PARPi-sensitive and PARPi-resistant HGSOC-PDXs in vivo. In this project, we have investigated the molecular and cellular response to CX-5461 in immortalised primary fallopian tube-dervied cell line and isogenically matched HR-proficient and HR-deficient HGSOC cell lines. We have identified CX-5461 leads to cell cycle arrest and sensecnce including the induction of senescene associated secretory phenotype in HR-proficient HGSOC cells. We have also demonstrated synthetic lethality between CX-5461 and HR-deficiency in HGSOC which is associated with genomic instability, activation of the caspase-2 pathway and cell death. We have shown that CX-5461 induces DNA damage response and replication stress in HR-deficient HGSOC cells raising the possibility of increasing the sensitivity of HGSOC to therapy by combining CX-5461 with chemotherapies or PARPi. Indeed, we have demonstrated that CX-5461 in combination with PARPi leads to significant reduction in clonogenic survival of HR-deficient and HR-proficient HGSOC cells compared to single agent treatment. Future work will focus on understanding the mechanisms underlying the cooperation between CX-5461 and PARPi in inhibiting survival of HGSOC cells. This will provide evidence for the potential of this combination therapy against HGSOC and faciliate clinical trials to improve patients outcome.