1. Academic Validation
  2. DNA-PK inhibition extends the therapeutic effects of Top2 poisoning to non-proliferating cells, increasing activity at a cost

DNA-PK inhibition extends the therapeutic effects of Top2 poisoning to non-proliferating cells, increasing activity at a cost

  • Sci Rep. 2023 Aug 1;13(1):12429. doi: 10.1038/s41598-023-39649-7.
Taixiang Wang 1 Alastair H Kyle 1 Jennifer H E Baker 1 Nannan A Liu 1 Judit P Banáth 1 Andrew I Minchinton 2
Affiliations

Affiliations

  • 1 Department of Integrative Oncology, BC Cancer Research Institute, 675 W 10th Ave, Vancouver, BC, V5Z 1L3, Canada.
  • 2 Department of Integrative Oncology, BC Cancer Research Institute, 675 W 10th Ave, Vancouver, BC, V5Z 1L3, Canada. aim@bccrc.ca.
Abstract

Type II Topoisomerase (Top2) poisoning therapy is used to treat a broad range of cancers via induction of double strand breaks (DSBs) in cells undergoing replication and transcription. Preventing the repair of DSBs via inhibition of DNA-PK, an inhibitor of non-homologous end-joining (NHEJ), increases cell kill with Top2 poisons and has led to the initiation of several clinical trials. To elucidate the cellular mechanisms leading to synergistic activity of dual DNA-PK/Top2 inhibition we looked at their effects in cycling versus non-cycling cells, in 3D spheroids and in xenograft models. Combined DNA-PK/Top2 inhibition was found to not only increase the cell kill in proliferating cells, the cell population that is typically most vulnerable to Top2 poisoning, but also in non-proliferative but transcriptionally active cells. This effect was observed in both Cancer and normal tissue models, killing more cells than high concentrations of etoposide alone. The combination treatment delayed tumor growth in mice compared to Top2 poisoning alone, but also led to increased toxicity. These findings demonstrate sensitization of Top2β-expressing, non-cycling cells to Top2 poisoning by DNA-PK inhibition. Expansion of the target cell population of Top2 poison treatment to include non-proliferating cells via combination with DNA damage repair inhibitors has implications for efficacy and toxicity of these combinations, including for inhibitors of DNA-PK currently in clinical trial.

Figures
Products