CRISPR screens guide the way for PARP and ATR inhibitor biomarker discovery.

Abstract

DNA repair pathways are heavily studied for their role in cancer initiation and progression. Due to the large amount of inherent DNA damage in cancer cells, tumor cells profoundly rely on proper DNA repair for efficient cell cycle progression. Several current chemotherapeutics promote excessive DNA damage in cancer cells, thus leading to cell death during cell cycle progression. However, if the tumor has efficient DNA repair mechanisms, DNA-damaging therapeutics may not be as effective. Therefore, directly inhibiting DNA repair pathways alone and in combination with chemotherapeutics that cause DNA damage may result in improved clinical outcomes. Nevertheless, tumors can acquire resistance to DNA repair inhibitors. It is essential to understand the genetic mechanisms underlying this resistance. Genome-wide CRISPR screening has emerged as a powerful tool to identify biomarkers of resistance or sensitivity to DNA repair inhibitors. CRISPR knockout and CRISPR activation screens can be designed to investigate how the loss or overexpression of any human gene impacts resistance or sensitivity to specific inhibitors. This review will address the role of CRISPR screening in identifying biomarkers of resistance and sensitivity to DNA repair pathway inhibitors. We will focus on inhibitors targeting the PARP1 and ATR enzymes, and how the biomarkers identified from CRISPR screens can help inform the treatment plan for cancer patients.