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Small-molecule inhibition of CBX4/7 hypersensitises homologous recombination-impaired cancer to radiation by compromising CtIP-mediated DNA end resection
Osborne, Hugh C Foster, Benjamin M Al-Hazmi, Hazim Meyer, Stefan Larrosa, I. Schmidt, Christine K
Osborne, Hugh C
Foster, Benjamin M
Al-Hazmi, Hazim
Meyer, Stefan
Larrosa, I.
Schmidt, Christine K
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Abstract
The therapeutic targeting of DNA repair pathways is an emerging concept in cancer treatment. Compounds that target specific DNA repair processes, such as those mending DNA double-strand breaks (DSBs), are therefore of therapeutic interest. UNC3866 is a small molecule that targets CBX4, a chromobox protein, and a SUMO E3 ligase. As a key modulator of DNA end resection-a prerequisite for DSB repair by homologous recombination (HR)-CBX4 promotes the functions of the DNA resection factor CtIP. Here, we show that treatment with UNC3866 markedly sensitises HR-deficient, NHEJ-hyperactive cancer cells to ionising radiation (IR), while it is non-toxic in selected HR-proficient cells. Consistent with UNC3866 targeting CtIP functions, it inhibits end-resection-dependent DNA repair including HR, alternative end joining (alt-EJ), and single-strand annealing (SSA). These findings raise the possibility that the UNC3866-mediated inhibition of end resection processes we define highlights a distinct vulnerability for the selective killing of HR-ineffective cancers.
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Date
2024
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Article
Citation
Osborne HC, Foster BM, Al-Hazmi H, Meyer S, Larrosa I, Schmidt CK. Small-Molecule Inhibition of CBX4/7 Hypersensitises Homologous Recombination-Impaired Cancer to Radiation by Compromising CtIP-Mediated DNA End Resection. CANCERS. 2024 JUN;16(11).