GENECADD · GEnetic NEtworks as a tool for anti-CAncer Drug Development

Although several therapies target cellular pathways, current small molecules drug discovery is based on identification of inhibitors to single proteins, without knowledge of whether they are the most advantageous target. The objective of this proposal is to develop a novel method for drug discovery, combining phenotypic cell based screens with functional genetic networks to determine the molecular mechanisms of numerous small molecule inhibitors. This method will enable identification of numerous distinct inhibitors of a particular pathway, as well as providing their molecular mechanism.Cancer cells harbour gene mutations that make them more reliant on other cellular pathways for survival. Such cellular pathways can be targeted to selectively kill the cancer cells using the concept of synthetic lethality. In this project we want to identify inhibitors of homologous recombination to target cancer using synthetic lethality.To establish a functional genetic network for homologous recombination, we will first identify all recombination proteins using multiple genome-wide RNAi screens. Then the synthetic sick or lethal interaction map between all recombination proteins is determined by co-depletion of these. Such synthetic sick or lethal network will identify numerous putative targets for anti-cancer treatment. Importantly, using this network for chemical-genetic functional interactions will assist in determinating of the molecular mechanisms of inhibitors. Chemical-genetic networks based on synthetic sickness or lethality can potentially change future drug discovery methods as well as providing new mechanistic insights into the field of toxicology.