Osborne Hugh C, Foster Benjamin M, Al-Hazmi Hazim, Meyer Stefan, Larrosa Igor, Schmidt Christine K
Manchester Cancer Research Centre (MCRC), Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health (FBMH), University of Manchester, 555 Wilmslow Road, Manchester M20 4GJ, UK.
Department of Paediatric and Adolescent Oncology, Royal Manchester Children's Hospital, Manchester M13 9WL, UK.
Cancers (Basel). 2024 Jun 6;16(11):2155. doi: 10.3390/cancers16112155.
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.
DNA修复途径的治疗靶向是癌症治疗中一个新兴的概念。因此，靶向特定DNA修复过程的化合物，如那些修复DNA双链断裂（DSB）的化合物，具有治疗意义。UNC3866是一种靶向CBX4的小分子，CBX4是一种染色盒蛋白，也是一种SUMO E3连接酶。作为DNA末端切除的关键调节因子——同源重组（HR）修复DSB的前提条件——CBX4促进DNA切除因子CtIP的功能。在这里，我们表明，用UNC3866处理可使HR缺陷、NHEJ高活性的癌细胞对电离辐射（IR）明显敏感，而在选定的HR proficient细胞中它是无毒的。与UNC3866靶向CtIP功能一致，它抑制包括HR、替代末端连接（alt-EJ）和单链退火（SSA）在内的依赖末端切除的DNA修复。这些发现增加了一种可能性，即我们定义的UNC3866介导的末端切除过程抑制突出了选择性杀死HR无效癌症的独特脆弱性。
