A cell-penetrating, anti-DNA antibody that inhibits DNA repair and potentiates cancer therapy

Rsrch Assoc Ther Radiology
15 York St, New Haven, CT 06510-3221

3E10 is a cell penetrating non-toxic anti-DNA antibody.  We have previously found that 3E10 sensitizes cancer cells to doxorubicin and sensitizes both cancer cells and human tumor xenografts to ionizing radiation. We recently found that 3E10 sensitizes cancer cells to cisplatin as well. Mechanistically, we find that 3E10 activates ATR resulting in phosphorylation of Chk1 suggesting that 3E10 induces replication stress.  We also observe a mild induction of ATM by 3E10 resulting in Chk2 phosphorylation.  Using cell-based assays, we demonstrate that 3E10 partially inhibits key double strand break repair pathways: homology-directed repair (HDR), single strand annealing (SSA), and non-homologous end joining (NHEJ).  We previously found that 3E10 is synthetically lethal to BRCA2-deficient cells.  Here we show that 3E10 is also synthetically lethal to hypoxic cancer cells.  We hypothesize that this effect may be due to replication stress from 3E10 combined with decreased Rad51 function, since our previous work showed that Rad51 is decreased in hypoxia. The work presented here provides further evidence that 3E10, either alone or in combination with radiation or chemotherapy, could lead to a new strategy in the treatment of cancer.