Targeting Non-homologous and Alternative End Joining Repair to Enhance Cancer Radiosensitivity

Area of Science:

• Oncology
• Molecular Biology
• Radiotherapy

Background:

• Radiotherapy induces DNA double-strand breaks (DSBs) to kill cancer cells.
• Modulating DSB repair is a key strategy for radiosensitization.
• Tumor-selective interventions are needed to avoid normal tissue toxicity.

Purpose of the Study:

• To review error-prone DSB repair mechanisms, focusing on end joining (EJ) pathways.
• To explore the therapeutic potential of targeting NHEJ and a-EJ for radiosensitization.
• To summarize the current status and challenges of targeting EJ pathways in cancer therapy.

Main Methods:

• Review of scientific literature on DSB repair mechanisms, particularly NHEJ and a-EJ.
• Analysis of therapeutic targets within EJ pathways: DNA-PKcs for NHEJ and Pol θ for a-EJ.
• Discussion of preclinical insights and clinical investigation status.

Main Results:

• Non-homologous end joining (NHEJ) and alternative end joining (a-EJ) are efficient, error-prone DSB repair pathways.
• Both NHEJ and a-EJ can be upregulated in cancer, making them attractive therapeutic targets.
• Targetable pioneer factors include DNA-PKcs (NHEJ) and Pol θ (a-EJ).

Conclusions:

• Targeting NHEJ and a-EJ offers a promising strategy for selective radiosensitization in cancer.
• Overcoming challenges and exploring opportunities in targeting these pathways is crucial.
• Leveraging insights into altered DSB repair programs in cancer supports clinical investigation.