Nonhomologous End-Joining Can Be Pharmacologically Inhibited

Hyperactive double-strand break (DSB) repair pathways can allow tumors to withstand genotoxic insult, thus conferring resistance to DNA damaging agents. As one of the major DSB repair pathways, nonhomologous end-joining(NHEJ) represents an attractive target for sensitizing cancer cells to DNA damage, but specific pharmacologic inhibition of the core NHEJ machinery has not yet been possible. Srivastava and colleagues built a homology-based representative 3-dimensional model of the DNA binding domain of human ligase IV, the enzyme that mediates joining of free DNA strands during NHEJ, and used in silico docking to predict compounds that would compete with damaged DNA for ligase IV binding. This approach identified 5,6-bis(benzylideneamino)-2-mercapto-pyrimidin-4-ol (SCR7), which indeed bound the ligase IV DNA binding domain and blocked ligase IV activity in a cell-free extract-based system. In cancer cell lines, SCR7 suppressed NHEJ-mediated repair, resulting in the accumulation of DSBs, increased apoptotic cell death, and reduced proliferation of multiple cell lines to varying degrees at micromolar concentrations in a ligase IV–dependent manner. SCR7 was well tolerated in mice although it led to a reversible reduction in lymphocytes due to inhibition of NHEJ-mediated V(D)J recombination. SCR7 prolonged survival by either inducing tumor regression or stopping tumor growth in 3 of 4 mouse tumor models tested. Interestingly, combining SCR7 with radiation or a DSB-inducing agent blocked the growth of xenografted tumors that did not respond to SCR7 alone and further increased DSB accumulation. Although future work is needed to understand the determinants of response to ligase IV inhibition, the identification of this lead compound shows that pharmacologic inhibition of NHEJ is feasible and may block tumor progression alone or in combination with radiation or chemotherapy.

Srivastava M, Nambiar M, Sharma S, Karki SS, Goldsmith G, Hegde M, et al. An inhibitor of nonhomologous end-joining abrogates double-strand break repair and impedes cancer progression. Cell 2012;151:1474–87.

Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.