DNA-PK inhibition synergizes with oncolytic virus M1 by inhibiting antiviral response and potentiating DNA damage

Xiao Xiao1,2, Jiankai Liang2, Chunlong Huang3

  • 1Institute of Clinical Medicine, The First Affiliated Hospital, University of South China, Hengyang, 421001, China.

Nature Communications
|October 20, 2018
PubMed

Insights

Combining DNA-dependent protein kinase (DNA-PK) inhibitors with oncolytic virus M1 enhances cancer cell killing. This strategy overcomes resistance to oncolytic virotherapy by boosting viral replication and tumor cell apoptosis.

Area of Science:

  • Oncology
  • Virology
  • Cancer Therapeutics

Background:

  • Oncolytic virotherapy utilizes replication-competent viruses to selectively target and destroy cancer cells.
  • Therapeutic efficacy of oncolytic viruses (OVs) can be variable, necessitating combination strategies to overcome resistance.
  • The antiviral response, including interferon transcription, can limit OV effectiveness.

Purpose of the Study:

  • To identify strategies to overcome resistance to oncolytic virotherapy.
  • To evaluate the combination of DNA-dependent protein kinase (DNA-PK) inhibition with oncolytic virus M1 (OV M1) for cancer treatment.

Main Methods:

  • Anticancer drug screening was performed to identify sensitizing agents for OV M1.
  • DNA-dependent protein kinase inhibitor (DNA-PKI) was tested in combination with OV M1.
  • Therapeutic effects were assessed in refractory cancer models in vivo and in patient tumor samples.

Main Results:

  • DNA-PK inhibition sensitized cancer cells to OV M1, improving therapeutic outcomes.
  • DNA-PK inhibition abolished the M1 virus-induced interferon response, enhancing viral replication in malignancies.
  • DNA-PK inhibition promoted virus-induced DNA damage response, increasing tumor cell apoptosis.

Conclusions:

  • DNA-PK inhibition is a viable strategy to enhance the efficacy of oncolytic virotherapy.
  • The combination of DNA-PKI and OV M1 demonstrates potential as a novel cancer treatment.
  • Targeting DNA-PK can overcome resistance mechanisms associated with oncolytic virus therapy.

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