Cancer esearch apeutics , Targets , and Chemical Biology textual Synthetic Lethality of Cancer Cell Kill Based R he Tumor Microenvironment

Downlo te and chronic hypoxia exists within the three-dimensional microenvironment of solid tumors and therapy resistance, genetic instability, and metastasis. Replicating cells exposed to either severe hypoxia (16 hours with 0.02% O2) followed by reoxygenation or moderate chronic hypoxia (72 hours .2% O2) treatments have decreased homologous recombination (HR) protein expression and funcs HR defects are synthetically lethal with poly(ADP-ribose) polymerase 1 (PARP1) inhibition, we ted the sensitivity of repair-defective hypoxic cells to PARP inhibition. Although PARP inhibition did not affect HR expression or function, we observed increased clonogenic killing in HR-deficient ic cells following chemical inhibition of PARP1. This effect was partially reversible by RAD51 oversion. PARP1 murine embryonic fibroblasts (MEF) showed a proliferative disadvantage under hypassing when compared with PARP1 MEFs. PARP-inhibited hypoxic cells accumulated γH2AX and foci as a consequence of altered DNA replication firing during S phase–specific cell killing. In supf this proposed mode of action, PARP inhibitor–treated xenografts displayed increased γH2AX and d caspase-3 expression in RAD51-deficient hypoxic subregions in vivo, which was associated with sed ex vivo clonogenic survival following experimental radiotherapy. This is the first report of secell killing of HR-defective hypoxic cells in vivo as a consequence of microenvironment-mediated xtual synthetic lethality.” As all solid tumors contain aggressive hypoxic cells, this may broaden the l utility of PARP and DNA repair inhibition, either alone or in combination with radiotherapy and clinica chemotherapy, even in tumor cells lacking synthetically lethal, genetic mutations. Cancer Res; 70(20); 8045–54.