Research progress in synthetic lethality targeting DNA repair defects / 肿瘤

ABSTRACT

The concept of synthetic lethality is defined as a genetic interaction of two non-allelic and non-lethal genes that when mutated simultaneously results in cell death, which has been proposed as a potential way to develop novel antitumor approaches. A new therapeutic approach targeting DNA repair defective genes may remarkably promote the antitumor efficacy based on the mechanism of tumorigenesis induced by DNA repair defects. Previous studies have demontrated that BRCA1 (breast cancer susceptibility gene 1)/BRCA2 or PTEN (phosphatase and tensin homolog deleted on chromosome 10) gene mutation with PARP [poly(ADP-ribose) polymerase] inhibitors could lead to killing effect in cancer cells; deletion of MSH2 (mutS homolog 2) gene with inhibiton of proofreading activity of DNA polβ (polymerase β) and the deletion of MLH1 (mutL homolog 1) gene with inhibiton of proofreading activity of DNA polγ could both lead to killing effect in cancer cells with MMR (mismatch repair) deficiency. PINK1 (PTEN-induced putative kinase 1) may be a potential therapeutic target for the treatment of MMR-deficient cancers with deletion of MSH2, MLH1 or MSH6 gene based on the theory of synthetic lethality. This review descibes the synthetic lethality associated with DNA repair defects. Copyright © 2013 by TUMOR.