Synthetic lethality (see also: Unit 5) is a recent concept, which is based on the phenomenon that cancer cells need to adapt major signaling pathways to the mutations that caused the cancer to emerge. These adaptations allow the cancer cells to escape programmed cell death, which otherwise would be triggered, if the cell recognizes that it "became" a cancer cell. This phenomenon is commonly referred to as oncogene or pathway addiction of cancer cells. Synthetic lethality means that blocking these addiction pathways causes lethality only to cancer cells, but not to normal cells, because the latter ones are not addicted. Theoretically, it may be possible to project this concept to CSCs in order to achieve their selective elimination.
This subproject explores a particular drug target, for which previous data indicated that is causes synthetic lethality to cancer cells. The main goal is to determine, whether addressing this drug target also causes synthetic lethality at the level of the CSCs in order to test the underlying concepts. Besides that, we use this system to derive general rules for the design of synthetic lethal nucleic acid-based drugs regarding selectivity, reduction of unspecific toxicity, stability and efficacy.
Fig 1: The concept of synthetic lethality: a cancer related mutation in one gene alone does not affect cell viability, but a knock-down of a second gene leads to cell death. This allows to specifically target cancer cells.