title: PARP Inhibitors in Clinical Use Induce Genomic Instability in Normal Human Cells.
abstract: 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.
authors.affiliation: Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.|Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Ito
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Conleth G
authors.initials: CG
authors.lastname: Murphy
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Doubrovina
authors.affiliation: Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Maria
authors.initials: M
authors.lastname: Jasin
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Moynahan
mesh_terms: D001562:Benzimidazoles / Q000009:adverse effects*; D002869:Chromosome Aberrations / Q000187:drug effects*; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D015870:Gene Expression; D042822:Genomic Instability / Q000187:drug effects*; D059765:Homologous Recombination; D006801:Humans; D007621:Karyotyping; D010793:Phthalazines / Q000009:adverse effects*; D010879:Piperazines / Q000009:adverse effects*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000009:adverse effects*; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D012854:Sister Chromatid Exchange / Q000187:drug effects*
chemical_list: D001562:Benzimidazoles; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib; D011065:Poly(ADP-ribose) Polymerases; D002945:Cisplatin; C531550:olaparib