An Inhibitor of Nonhomologous End-Joining Abrogates Double-Strand Break Repair and Impedes Cancer Progression
Menée à l'aide de modèles murins, cette étude évalue l'activité antitumorale d'un composé appelé SCR7, un inhibiteur de l'ADN ligase IV, seul ou en combinaison avec divers agents de chimiothérapie
DNA Ligase IV is responsible for sealing of double-strand breaks (DSBs) during nonhomologous end-joining (NHEJ). Inhibiting Ligase IV could result in amassing of DSBs, thereby serving as a strategy toward treatment of cancer. Here, we identify a molecule, SCR7 that inhibits joining of DSBs in cell-free repair system. SCR7 blocks Ligase IV-mediated joining by interfering with its DNA binding but not that of T4 DNA Ligase or Ligase I. SCR7 inhibits NHEJ in a Ligase IV-dependent manner within cells, and activates the intrinsic apoptotic pathway. More importantly, SCR7 impedes tumor progression in mouse models and when coadministered with DSB-inducing therapeutic modalities enhances their sensitivity significantly. This inhibitor to target NHEJ offers a strategy toward the treatment of cancer and improvement of existing regimens. º SCR7, a Ligase IV inhibitor, blocks NHEJ in vitro and in vivo º Inhibitor interferes with DNA binding domain association with double-strand breaks º SCR7 impedes progression of tumors in mouse models, leading to enhanced lifespan º Persistent breaks potentiate the effects of radio- and chemotherapy Inhibition of Ligase IV, a key factor in nonhomologous end-joining, fosters apoptosis, impairs tumor growth, and enhances the efficacy of other chemotherapeutics in mouse models of cancer.