APOBEC3 deaminase drives acquired anticancer targeted therapy resistance

Abstract

Despite the huge success of targeted therapy in the last two decades, their clinical application has been hindered by the emergence of drug resistance. Early investigation into the mutation patterns of cancer genomes have revealed the role of APOBEC in tumor mutagenesis. However, the role of APOBE in tumor evolution and the development of acquired therapy resistance remains unclear. Recently two research groups signified therapy-induced APOBEC as a key mutagenesis machinery involved in the formation of double-strand DNA breaks and enhancing genomic instability to promote tumor evolution. Most of these mutations are observed in driver oncogenes, making cancer cells independent of their conventional driver genes/pathways leading to acquired therapy resistance. Overall, the data indicate that induction of APOBEC in response to targeted therapy drives the evolution of resistant clones and the inhibition of APOBEC might serve as a new strategy for the prevention of acquired therapy resistance in cancer.