PARP Inhibitor Resistance: A Tug-of-War in BRCA-Mutated Cells

作者：Sylvie M. Noordermeer, Haico van Attikum · 发表于：Trends in Cell Biology · 年份：2019 · DOI：10.1016/j.tcb.2019.07.008 · 被引用次数：476 · 研究领域：PARP inhibition in cancer therapy、DNA Repair Mechanisms、CRISPR and Genetic Engineering

Poly-(ADP)-ribose polymerase (PARP) inhibition is synthetic lethal with deficiency for homologous recombination (HR), a pathway essential for DNA double-strand break repair. PARP inhibitors (PARPi) therefore hold great promise for the treatment of tumors with disruptive mutations in BRCA1/2 or other HR factors. Unfortunately, PARPi resistance has proved to be a major problem in the clinic. Knowledge about PARPi resistance is expanding quickly, revealing four main mechanisms that alter drug availability, affect (de)PARylation enzymes, restore HR, or restore replication fork stability. We discuss how studies on resistance mechanisms have yielded important insights into the regulation of DNA double-strand break (DSB) repair and replication fork protection, and how these studies could pave the way for novel treatment options to target resistance mechanisms or acquired vulnerabilities.