PARP Inhibitors in Clinical Use Induce Genomic Instability in Normal Human Cells

• Published in: PloS one 2016-07, Vol.11 (7), p.e0159341
• Main Authors: Ito, Shuhei, Murphy, Conleth G, Doubrovina, Ekaterina, Jasin, Maria, Moynahan, Mary Ellen
• Format: Article
• Language: English
• Subjects: Aberration; Adenosine diphosphate; ADP-ribosylation; Analysis; Benzimidazoles - adverse effects; Biology and Life Sciences; BRCA1 protein; BRCA2 protein; Breast cancer; Cancer; Cancer treatment; Chromosome Aberrations - drug effects; Cisplatin; Cisplatin - pharmacology; Clinical trials; Computer and Information Sciences; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA damage; DNA Damage - drug effects; DNA repair; DNA Repair - drug effects; Dose-Response Relationship, Drug; Double-strand break repair; Drug Synergism; Epithelial cells; Female; Gene Expression; Genomic instability; Genomic Instability - drug effects; Genotoxicity; Homologous Recombination; Homology; Humans; Hypersensitivity; Inhibitors; Karyotyping; Kinases; Lymphoid cells; Medical research; Medicine and Health Sciences; Mutation; Ovarian cancer; Phthalazines - adverse effects; Piperazines - adverse effects; Poly(ADP-ribose); Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerase Inhibitors - adverse effects; Poly(ADP-ribose) Polymerases - genetics; Poly(ADP-ribose) Polymerases - metabolism; Prostate cancer; Proteins; Repair; Ribose; Ribosylation; Risk factors; Rodents; Sister chromatid exchange; Sister Chromatid Exchange - drug effects; Stability; Targeted cancer therapy; Toxicity; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0159341

Poly(ADP-ribose) polymerases (PARPs) are the first proteins involved in cellular DNA repair pathways to be targeted by specific inhibitors for clinical benefit. Tumors harboring genetic defects in homologous recombination (HR), a DNA double-strand break (DSB) repair pathway, are hypersensitive to PARP inhibitors (PARPi). Early phase clinical trials with PARPi have been promising in patients with advanced BRCA1 or BRCA2-associated breast, ovary and prostate cancer and have led to limited approval for treatment of BRCA-deficient ovary cancer. Unlike HR-defective cells, HR-proficient cells manifest very low cytotoxicity when exposed to PARPi, although they mount a DNA damage response. However, the genotoxic effects on normal human cells when agents including PARPi disturb proficient cellular repair processes have not been substantially investigated. We quantified cytogenetic alterations of human cells, including primary lymphoid cells and non-tumorigenic and tumorigenic epithelial cell lines, exposed to PARPi at clinically relevant doses by both sister chromatid exchange (SCE) assays and chromosome spreading. As expected, both olaparib and veliparib effectively inhibited poly-ADP-ribosylation (PAR), and caused marked hypersensitivity in HR-deficient cells. Significant dose-dependent increases in SCEs were observed in normal and non-tumorigenic cells with minimal residual PAR activity. Clinically relevant doses of the FDA-approved olaparib led to a marked increase of SCEs (5-10-fold) and chromatid aberrations (2-6-fold). Furthermore, olaparib potentiated SCE induction by cisplatin in normal human cells. Our data have important implications for therapies with regard to sustained genotoxicity to normal cells. Genomic instability arising from PARPi warrants consideration, especially if these agents will be used in people with early stage cancers, in prevention strategies or for non-oncologic indications.