PARP inhibitors are less synthetically lethal in hypoxic conditions – AACR 2014

Immunocytochemical staining of stable BRCA1 KD SilenciX cell line

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.

Sources:

SilenciX®, novel stable knock-down cellular models to screen new molecular targets through the synthetic lethality approach  (“Experimental and Molecular Therapeutics” poster session – AACR 2014, San Diego) Abstract n° 3733
Eric Mennesson1, Anne-Marie Renault1, Isabelle Fixe1, Catherine Grillon2, Claudine Kiéda2, Nadia Normand1  (1/ tebu-bio – 2/ Centre de Biophysique Moléculaire CNRS UPR 4301 (France)).
Philippe Fixe, PhD
Written by Philippe Fixe, PhD
Philippe Fixe is Marketing Director at tebu-bio, passionate about innovation and R&D in Life sciences, Biotechnology, Medical research, Drug discovery, and also a keen photographer.