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.
Abstract:
Oncolytic virotherapy is a promising therapeutic strategy that uses replication-competent viruses to selectively destroy malignancies. However, the therapeutic effect of certain oncolytic viruses (OVs) varies among cancer patients. Thus, it is necessary to overcome resistance to OVs through rationally designed combination strategies. Here, through an anticancer drug screening, we show that DNA-dependent protein kinase (DNA-PK) inhibition sensitizes cancer cells to OV M1 and improves therapeutic effects in refractory cancer models in vivo and in patient tumour samples. Infection of M1 virus triggers the transcription of interferons (IFNs) and the activation of the antiviral response, which can be abolished by pretreatment of DNA-PK inhibitor (DNA-PKI), resulting in selectively enhanced replication of OV M1 within malignancies. Furthermore, DNA-PK inhibition promotes the DNA damage response induced by M1 virus, leading to increased tumour cell apoptosis. Together, our study identifies the combination of DNA-PKI and OV M1 as a potential treatment for cancers.
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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