Clinical use and mechanisms of resistance for PARP inhibitors in homologous recombination-deficient cancers.

Cells are continuously subjected to DNA damaging agents. DNA damages are repaired by one of the many pathways guarding genomic integrity. When one or several DNA damage pathways are rendered inefficient, cells can accumulate mutations, which modify normal cellular pathways, favoring abnormal cell growth. This supports malignant transformation, which can occur when cells acquire resistance to cell cycle checkpoints, apoptosis, or growth inhibition signals. Mutations in genes involved in the repair of DNA double strand breaks (DSBs), such as BRCA1, BRCA2, or PALB2, significantly increase the risk of developing cancer of the breast, ovaries, pancreas, or prostate. Fortunately, the inability of these tumors to repair DNA breaks makes them sensitive to genotoxic chemotherapies, allowing for the development of therapies precisely tailored to individuals' genetic backgrounds. Unfortunately, as with many anti-cancer agents, drugs used to treat patients carrying a BRCA1 or BRCA2 mutation create a selective pressure, and over time tumors can become drug resistant. Here, we detail the cellular function of tumor suppressors essential in DNA damage repair pathways, present the mechanisms of action of inhibitors used to create synthetic lethality in BRCA carriers, and review the major molecular sources of drug resistance. Finally, we present examples of the many strategies being developed to circumvent drug resistance.

Translational oncology. 2021 Jan 27 [Epub ahead of print]

Dawn C Janysek, Jennifer Kim, Pascal H G Duijf, Eloïse Dray

School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States., Queensland University of Technology, IHBI at the Translational Research Institute, Brisbane, QLD, Australia; Centre for Data Science, Queensland University of Technology, Brisbane, QLD, Australia; University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia., Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States; Mays Cancer Center, UT Health San Antonio MD Anderson, San Antonio, TX, United States. Electronic address: .