Abstract
High-grade serous ovarian cancer (HGSOC) accounts for the majority of ovarian cancer and has a dismal prognosis. PARP inhibitors (PARPi) have revolutionized disease management of patients with homologous recombination (HR) DNA repair-deficient HGSOC. However, acquired resistance to PARPi by complex mechanisms including HR restoration and stabilisation of replication forks is a major challenge in the clinic. Here, we demonstrate CX-5461, an inhibitor of RNA polymerase I transcription of ribosomal RNA genes (rDNA), induces replication stress at rDNA leading to activation of DNA damage response and DNA damage involving MRE11-dependent degradation of replication forks. CX-5461 cooperates with PARPi in exacerbating DNA damage and enhances synthetic lethal interactions of PARPi with HR deficiency in HGSOC-patient-derived xenograft (PDX) in vivo. We demonstrate CX-5461 has a different sensitivity spectrum to PARPi and destabilises replication forks irrespective of HR pathway status, overcoming two well-known mechanisms of resistance to PARPi. Importantly, CX-5461 exhibits single agent efficacy in PARPi-resistant HGSOC-PDX. Further, we identify CX-5461-sensitivity gene expression signatures in primary and relapsed HGSOC. Therefore, CX-5461 is a promising therapy alone and in combination therapy with PARPi in HR-deficient HGSOC. CX-5461 is also an exciting treatment option for patients with relapsed HGSOC tumors that have poor clinical outcome.
Abbreviations
- ATM
- Ataxia telangiectasia mutated
- ATR
- Ataxia telangiectasia and Rad3
- BER
- Base excision repair
- CHK1/2
- Checkpoint kinases 1/2
- DDR
- DNA damage response
- DSBs
- double strand breaks
- DDR therapy
- DNA repair and DDR inhibitors
- 5’ETS
- External spliced region
- GI
- Growth inhibition
- GQ
- G-quadruplex DNA
- HGSOC
- High-grade serous ovarian cancer
- HR
- homologous recombination
- HRD
- HR deficiency
- IR
- ionizing radiation
- KO
- Knockout
- TTH
- time to harvest
- NHEJ
- Non-homologous end joining
- OVCA
- Ovarian cancer
- PDX
- Patient-derived xenografts
- PARP
- Poly-(ADP-ribose) polymerase
- PARPi
- PARP inhibitors
- Pol I
- RNA polymerase I
- RPA
- replication protein A
- rRNA
- ribosomal RNA
- rDNA
- rRNA genes
- R-loops
- RNA DNA hybrids
- ssDNA
- single-strand DNA
- TSS
- Transcription start site
- UBF
- upstream binding transcription factor