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Mol Cancer Ther. 2015 Feb;14(2):326-42. doi: 10.1158/1535-7163.MCT-14-0765. Epub 2014 Dec 15.

Identification of novel radiosensitizers in a high-throughput, cell-based screen for DSB repair inhibitors.

Author information

1
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
2
High Throughput and Spectroscopy Resource Center, Rockefeller University, New York, New York.
3
Section of Medical Oncology, Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut.
4
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut.
5
Flow Cytometry Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York.
6
Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
7
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York. ranjit.bindra@yale.edu powells@mskcc.org.
8
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut. ranjit.bindra@yale.edu powells@mskcc.org.

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.

PMID:
25512618
PMCID:
PMC4326563
DOI:
10.1158/1535-7163.MCT-14-0765
[Indexed for MEDLINE]
Free PMC Article

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