Advances in therapeutic targeting of the DNA damage response in cancer

Abstract

The DNA damage response (DDR) is a series of pathways and processes required to repair lesions to DNA. These pathways range from repairing strand breaks to the double helix, damaged bases formed after oxidation or deamination, inaccurate DNA replication resulting in mispaired base alignment, intrastrand crosslinks that trigger cell death, and a plethora of other genomic insults. The DDR is believed to be a critical component of radio and chemoresistance in many cancers as well, with the tumor's ability to repair therapy induced damage being an important tool used to survive traditional chemotherapeutic agents. Here we summarize advances made in specifically targeting DDR proteins in cancer therapy and project on the potential breakthroughs and pitfalls to arise as the field progresses.

Fig. 1

Synthetic lethality between BRCA mutation and PARP1 inhibition.

Fig. 2

The nature of Cas9 mediated lesions determines repair pathway engagements. Summary of Bothmer et al. [57] findings describing WT Cas9 inducing the “classical” DSB repaired predominantly by NHEJ, D10A Cas9 resulting in a 5′ overhang that frequently induces HR, and N863A Cas9 that produces a 3′ overhang that engages translesion synthesis dependent microhomology-mediated end joining (MMEJ).