Abstract 3733: SilenciX®, novel stable knock-down cellular models to screen new molecular targets through the synthetic lethality approach

Abstract

Abstract PARP inhibitors are promising therapeutic drugs for cancers harboring BRCA1 and BRCA2 mutations. PARP is involved in the Base Excision Repair (BER) DNA repair pathway. Tumors with BRCA mutations are deficient in Homologous Recombination (HR), another DNA repair pathway. To maintain DNA integrity and prevent cell death, at least one one of the BER or HE pathways must be functional, while the other may be inhibited or silenced (eg. mutation, drug). In drug discovery, Synthethic Lethality (SL) used a cancer mutation and a drug in combination to cause the tumor cell's death. SL is thus a promising approach to find new druggable targets by controlling the HR and BER DNA repair pathways in order to selectively kill mutated cancer cells. However, the main technical hurdle in SL approaches is to easily identify cancer-specific molecular interaction in various cancer types, while using robust and validated experimental cellular models. In this presentation we demonstrate how the SilenciX® technology meets SL experimental requirements. BRCA1 and BRCA2 Silencix® cells were treated with PARP1 inhibitors (Olaparib, Veliparib, Rucaparib) and with Gemcitabine. All inhibitors except Gemcitabine were synthetic lethal in BRCA1 SilenciX® cell lines. To mimic the cancer micro-environement, the model was tested under hypoxic conditions. We conclude that SilenciX® cell lines are ingenious gene-specific Knock Down engineered cell lines using a new pEBV derived plasmid, avoiding integration and off-target effects, suitable for a broad range of synthetic lethality studies. Citation Format: Eric Mennesson, Anne-Marie Renault, Isabelle Fixe, Catherine GRILLON, Claudine Kiéda, Nadia Normand. SilenciX®, novel stable knock-down cellular models to screen new molecular targets through the synthetic lethality approach. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3733. doi:10.1158/1538-7445.AM2014-3733