Synthetic lethal interactions for kinase deficiencies to DNA damage chemotherapeutics

Abstract

Kinases are signaling enzymes that regulate diverse cellular processes. As such, they are frequently mutated in cancer and therefore represent important targets for drug discovery. However, until recently, systematic approaches to identify vulnerabilities and resistances of kinases to DNA-damaging chemotherapeutics have not been possible, partially due to the lack of appropriate technologies. With the advent of CRISPR-Cas9, a comprehensive study has investigated the cellular survival of more than 300 kinase-deficient isogenic cell lines to a diverse panel of DNA-damaging agents, enriched for chemotherapeutics. Here, we discuss how this approach has allowed for the rational development of combination therapies that are aimed at using synthetic lethal interactions between kinase deficiencies and DNA-damaging agents that are used as chemotherapeutics.