Contextual synthetic lethality: Repair-deficient hypoxic tumor cells are sensitized to poly(ADP-ribose) polymerase (PARP) inhibition

Acute and chronic hypoxia exists within the 3D microenvironment of solid tumors and drives therapy resistance, genetic instability and metastasis. Replicating cells exposed to either severe acute hypoxia (16 h with 0.02% O2) followed by reoxygenation or moderate chronic hypoxia (72 h with 0.2% O2) treatments had decreased RAD51 protein expression and homologous recombination (HR) function. As HR defects are synthetically lethal with poly(ADP‐ribose) polymerase 1 (PARP1) inhibition, we evaluated the sensitivity of HR‐defective hypoxic cells to PARP inhibition. Although PARP inhibition did not affect HR, we observed increased clonogenic killing in HR‐deficient hypoxic cells following inhibition or siRNA depletion of PARP1. PARP1−/− MEFs showed a proliferative disadvantage and a lack of cell adaption to hypoxia when compared to PARP1+/+ MEFs. PARP‐inhibited hypoxic cells accumulated H2AX and 53BP1 foci as a consequence of altered DNA replication firing leading to S phase‐specific cell killing. In support of this proposed mode of action, PARP inhibitor treated RKO xenografts showed increased H2AX‐positivity and cell death across hypoxic cell gradients in subregions with suppressed RAD51 expression. We conclude that the repair defects observed in hypoxic cells can sensitize hypoxic cells to PARP inhibition as a consequence of microenvironment‐mediated “contextual synthetic lethality”. As all solid tumors contain hypoxic cells, this may broaden the clinical utility of PARP inhibition in cancer therapy. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A115.