Exploiting hypoxia for anti-cancer therapy using a synthetic context lethality approach
Ester Hammond
University of Oxford, UK
Regions of low oxygen or hypoxia occur in most if not all solid tumours. This occurs as a result of poor and inefficient tumour vasculature. The significance of this is that hypoxic cells show increased resistance to chemotherapy and radiotherapy as well as having a more aggressive/metastatic phenotype. Periods of rapid reoxygenation also occur due to fluctuating tumour-oxygen tensions and contribute to the biological response. Hypoxia has been demonstrated to repress DNA repair pathways such as homologous recombination. A number of proteins essential to homologous recombination have been shown to be down-regulated both transcriptionally and translationally. As homologous recombination defects, typified by loss of BRCA signalling, are synthetically lethal with poly(ADP-ribose) polymerase 1 (PARP1) inhibition, we evaluated the sensitivity of hypoxic HR-defective cells to PARP1 inhibition. Both acute hypoxia chronic hypoxia treatments decreased homologous recombination protein expression.
Our studies, including clonogenic assays confirmed this led to an increased sensitivity of hypoxic cells to PARP deficiency using siRNA or pharmacologic inhibition. Hypoxic cells were preferentially sensitized in S phase suggesting synthetic toxicity is, in part, related to PARP inhibition during DNA replication. We conclude that hypoxia and reoxygenation can sensitize 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.
