Synthetic Genetic Targeting of Genome Instability in Cancer

Abstract

Cancer is a leading cause of death throughout the World. A limitation of many current chemotherapeutic approaches is that their cytotoxic effects are not restricted to cancer cells, and adverse side effects can occur within normal tissues. Consequently, novel strategies are urgently needed to better target cancer cells. As we approach the era of personalized medicine, targeting the specific molecular defect(s) within a given patient’s tumor will become a more effective treatment strategy than traditional approaches that often target a given cancer type or sub-type. Synthetic genetic interactions are now being examined for their therapeutic potential and are designed to target the specific genetic and epigenetic phenomena associated with tumor formation, and thus are predicted to be highly selective. In general, two complementary approaches have been employed, including synthetic lethality and synthetic dosage lethality, to target aberrant expression and/or function associated with tumor suppressor genes and oncogenes, respectively. Here we discuss the concepts of synthetic lethality and synthetic dosage lethality, and explain three general experimental approaches designed to identify novel genetic interactors. We present examples and discuss the merits and caveats of each approach. Finally, we provide insight into the subsequent pre-clinical work required to validate novel candidate drug targets.

Predicting Cancer-Specific Vulnerability via Data-Driven Detection of Synthetic Lethality

“…We expanded DAISY to also detect synthetic dosage lethality (Sajesh et al, 2013). While two genes form an SL pair if the inactivation of one gene renders the other essential, two genes form a synthetic dosage lethal (SDL) pair if the overactivity of one of them renders the other gene essential.…”

Building high-resolution synthetic lethal networks: a ‘Google map’ of the cancer cell

“…Years of experimental knowledge have enabled the research community to predict potential NGIs that could be translated for therapeutics [37]. One of the most explored areas of SL-SDL interactions that preferentially kill cancer cells by exploiting dependencies that are not shared by normal tissue are those involved in the DNA damage response or checkpoint control pathways.…”

The enigmatic oncogene and tumor suppressor‐like properties of RAD54B: Insights into genome instability and cancer

“…Synthetic genetic approaches aim to exploit the aberrant genetics (e.g., mutation, deletion, or amplification) associated with cancer development, and are predicted to induce highly specific killing in cancer cells while minimizing side effects within normal cells. Synthetic genetic interactions have been studied extensively in model organisms such as budding yeast and are now being explored for their therapeutic potential in various cancer contexts. RAD54B is an excellent candidate to exploit through synthetic genetic approaches as alterations in expression and function occur in a wide variety of cancers that by definition, serve to genetically distinguish cancer cells from healthy surrounding cells and tissues.…”

“…The term synthetic lethality was first coined by Theodore Dobzhansky in 1946, and described the lethal genetic interaction observed when two independently viable homologous chromosomes were allowed to recombine in Drosophila pseudoobscura . Since the original description, the definition has been refined and is now used to describe a rare and lethal combination of two independently viable mutations (Figure B). Simply put, synthetic lethality describes a genetic interaction in which the outcome of a specific mutation or deletion is influenced by the presence of a pre‐existing genetic alteration, such as those occurring in cancer.…”