Small-Molecule Inhibition of CBX4/7 Hypersensitises Homologous Recombination-Impaired Cancer to Radiation by Compromising CtIP-Mediated DNA End Resection.

Simple Summary: DNA damage occurs in healthy cells and cancer cells, but the quantity of damage and how efficiently it is repaired often differ between them. Due to genetic alterations, cancer cells can become 'addicted' to one or more forms of repair. This can be exploited by blocking DNA repair pathways that healthy cells can repair via redundant methods which are abrogated in cancer cells. Here, we identify such a scenario using a small molecule targeting CBX4, a protein key to a subset of DNA repair processes important for mending DNA double-strand breaks (DSBs). Consistent with the inhibition of these processes, treatment with the compound results in the selective killing of certain cancer cells when combined with ionizing radiation (IR). These findings raise the possibility that targeting CBX4 and/or the DSB repair pathways it regulates might be exploited more generally for the development of targeted anti-cancer strategies in the future. 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. [ABSTRACT FROM AUTHOR]