Targeting aberrant DNA double strand break repair in triple negative breast cancer with alpha particle emitter radiolabeled anti-EGFR antibody

The greater potential efficacy of alpha-particle emitter radiopharmaceutical therapy lies in the 3 to 8-fold greater biological effectiveness (RBE) of alpha particles relative to photon or beta-particle radiation. The greater RBE, however, generally applies to both tumor and normal tissue, thereby reducing efficacy. Since alpha particles typically cause DNA double strand breaks (DSBs), targeting tumors that are defective in DNA DSB repair would effectively increase the RBE, yielding a secondary, RBE-based differentiation between tumor and normal tissue that is complementary to conventional, delivery-based tumor targeting. In some triple negative breast cancer (ER-/PR-/HER-2-, TNBC) patients, both germline predisposed mutation or sporadic gene silencing in BRCA-1, a key gene in homologous recombination (HR) DSB repair, are well established. Such patients have few treatment options once the cancer has metastasized. In this study, we investigated the efficacy of alpha particle emitter, 213Bi labeled anti-EGFR antibody, Cetuximab, in TNBC cells that are defective in DNA DSB repair. 213Bi-Cetuximab was found to be significantly more effective in BRCA-1 mutated TNBC cell HCC1937. siRNA knockdown of BRCA-1 or DNA-PKcs, a key gene in non-homologous end joining (NHEJ) DSB repair, sensitized TNBC cells to 213Bi-Cetuximab. Furthermore, the small molecule inhibitor of DNA-PKcs, NU7441, also sensitized TNBC cells to alpha radiation. Both immunofluorescent staining of H2AX foci and Comet assay confirmed that enhanced RBE is caused by impaired DNA DSB repair. These data suggest a strategy for enhancing conventional receptor-mediated targeting with an additional, potentially synergistic radiobiological alpha-emitter targeting that could be applied to TNBC metastases.

SONG H.;  HOBBS Robert F.;  SHAO Chunbo;  BRUCHERTSEIFER Frank;  MORGENSTERN Alfred;  DEWEESE Tl;  SGOUROS G.;  HEDAYATI Mohammad; 

2013-10-09

AMER ASSOC CANCER RESEARCH

JRC76173

1535-7163,   

http://mct.aacrjournals.org/content/12/10/2043,    https://publications.jrc.ec.europa.eu/repository/handle/JRC76173,   

10.1158/1535-7163.MCT-13-0108,