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Updated: Apr 19, 2026
Author Spotlight: Developing Novel Anticancer Therapeutics Targeting the DNA Damage Response
Published on: June 14, 2024
Identification of novel radiosensitizers in a high-throughput, cell-based screen for DSB repair inhibitors
Alexander G Goglia1, Robert Delsite1, Antonio N Luz2
1Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
Abstract:
Most cancer therapies involve a component of treatment that inflicts DNA damage in tumor cells, such as double-strand breaks (DSBs), which are considered the most serious threat to genomic integrity. Complex systems have evolved to repair these lesions, and successful DSB repair is essential for tumor cell survival after exposure to ionizing radiation (IR) and other DNA-damaging agents. As such, inhibition of DNA repair is a potentially efficacious strategy for chemo- and radiosensitization. Homologous recombination (HR) and nonhomologous end-joining (NHEJ) represent the two major pathways by which DSBs are repaired in mammalian cells. Here, we report the design and execution of a high-throughput, cell-based small molecule screen for novel DSB repair inhibitors. We miniaturized our recently developed dual NHEJ and HR reporter system into a 384-well plate-based format and interrogated a diverse library of 20,000 compounds for molecules that selectively modulate NHEJ and HR repair in tumor cells. We identified a collection of novel hits that potently inhibit DSB repair, and we have validated their functional activity in a comprehensive panel of orthogonal secondary assays. A selection of these inhibitors was found to radiosensitize cancer cell lines in vitro, which suggests that they may be useful as novel chemo- and radio sensitizers. Surprisingly, we identified several FDA-approved drugs, including the calcium channel blocker mibefradil dihydrochloride, that demonstrated activity as DSB repair inhibitors and radiosensitizers. These findings suggest the possibility for repurposing them as tumor cell radiosensitizers in the future. Accordingly, we recently initiated a phase I clinical trial testing mibefradil as a glioma radiosensitizer.
Insights
Researchers screened 20,000 compounds to find novel inhibitors of DNA double-strand break (DSB) repair. They identified compounds that radiosensitize cancer cells, including FDA-approved drugs like mibefradil, suggesting repurposing potential.
Area of Science:
- Molecular Biology
- Cancer Research
- Drug Discovery
Background:
- Cancer therapies often induce DNA damage, particularly double-strand breaks (DSBs), necessitating robust repair mechanisms for tumor cell survival.
- Inhibiting DSB repair pathways, such as homologous recombination (HR) and nonhomologous end-joining (NHEJ), is a promising strategy for enhancing chemo- and radiosensitization.
- Identifying novel DSB repair inhibitors is crucial for developing more effective cancer treatments.
Purpose of the Study:
- To design and implement a high-throughput, cell-based small molecule screen for novel inhibitors of DSB repair.
- To identify compounds that selectively modulate NHEJ and HR repair pathways in tumor cells.
- To evaluate the potential of identified inhibitors as chemo- and radiosensitizers.
Main Methods:
- Miniaturization of a dual NHEJ and HR reporter system into a 384-well plate format.
- Screening of a diverse library of 20,000 small molecules to identify DSB repair modulators.
- Validation of hit compounds using orthogonal secondary assays and in vitro radiosensitization studies in cancer cell lines.
Main Results:
- Identification of novel small molecules that potently inhibit DSB repair.
- Validation of functional activity of identified inhibitors through comprehensive secondary assays.
- Demonstration that selected inhibitors radiosensitize cancer cell lines in vitro.
- Discovery of FDA-approved drugs, including mibefradil dihydrochloride, with DSB repair inhibitory and radiosensitizing activity.
Conclusions:
- The screen successfully identified novel DSB repair inhibitors with potential as chemo- and radiosensitizers.
- FDA-approved drugs, such as mibefradil, show promise for repurposing as tumor cell radiosensitizers.
- A Phase I clinical trial is underway to test mibefradil as a glioma radiosensitizer.
