PARP inhibitors are less synthetically lethal in hypoxic conditions – AACR 2014
Hypoxia has important effects on chemosensitivity of cancer cells and the synthetic lethal effects of drugs.
In a recent work presented during the “Experimental and Molecular Therapeutics” sessions at the AACR 2014, Claudine Kiéda’s and Nadia Normand’s teams showed that PARP inhibitors are less synthetically lethal in hypoxic conditions with increased IC50 and survival percentage at higher concentrations.
Synthetic Lethality (SL) is defined as when loss of two genes independently has no effect on viability, but simultaneous loss of both genes causes cell death.
In cancer research and drug discovery, SL is observed when the cancer mutation and the drug simultaneously inhibit two otherwise independent pathways, leading to cell death. The best known SL relationship is between BRCA1/2 mutation (tumors deficient in Homologous Recombination (HR) DNA Repair pathway) and PARP inhibitors (affecting the Base Excision Repair (BER) DNA Repair pathway).
In their work, Dr Kiéda and Dr Normand used already published in vitro stable BRCA1- and BRCA2-KD cell lines (SilenciX® technology) to measure the synthetic lethal efficiency of PARP inhibitors (Olaparib, Veliparib and Rucaparib) in both normoxic and hypoxic conditions. They demonstrate that the BRCA-KD SilenciX® cell lines are effective and convenient in vitro cellular models to design new cancer drug candidates through the SL approach in oxygen-controlled conditions to better mimick physioxia seen in solid tumors.