title: Therapeutic potential of the poly(ADP-ribose) polymerase inhibitor rucaparib for the treatment of sporadic human ovarian cancer.
abstract: Here, we investigate the potential role of the PARP inhibitor rucaparib (CO-338, formerly known as AG014699 and PF-01367338) for the treatment of sporadic ovarian cancer. We studied the growth inhibitory effects of rucaparib in a panel of 39 ovarian cancer cell lines that were each characterized for mutation and methylation status of BRCA1/2, baseline gene expression signatures, copy number variations of selected genes, PTEN status, and sensitivity to platinum-based chemotherapy. To study interactions with chemotherapy, we used multiple drug effect analyses and assessed apoptosis, DNA fragmentation, and γH2AX formation. Concentration-dependent antiproliferative effects of rucaparib were seen in 26 of 39 (67%) cell lines and were not restricted to cell lines with BRCA1/2 mutations. Low expression of other genes involved in homologous repair (e.g., BCCIP, BRCC3, ATM, RAD51L1), amplification of AURKA or EMSY, and response to platinum-based chemotherapy was associated with sensitivity to rucaparib. Drug interactions with rucaparib were synergistic for topotecan, synergistic, or additive for carboplatin, doxorubicin or paclitaxel, and additive for gemcitabine. Synergy was most pronounced when rucaparib was combined with topotecan, which resulted in enhanced apoptosis, DNA fragmentation, and γH2AX formation. Importantly, rucaparib potentiated chemotherapy independent of its activity as a single agent. PARP inhibition may be a useful therapeutic strategy for a wider range of ovarian cancers bearing deficiencies in the homologous recombination pathway other than just BRCA1/2 mutations. These results support further clinical evaluation of rucaparib either as a single agent or as an adjunct to chemotherapy for the treatment of sporadic ovarian cancer.
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
authors.forename: Maike
authors.initials: M
authors.lastname: Ihnen
authors.forename: Christine
authors.initials: C
authors.lastname: zu Eulenburg
authors.forename: Teodora
authors.initials: T
authors.lastname: Kolarova
authors.forename: Jing Wei
authors.initials: JW
authors.lastname: Qi
authors.forename: Kanthinh
authors.initials: K
authors.lastname: Manivong
authors.forename: Meenal
authors.initials: M
authors.lastname: Chalukya
authors.forename: Judy
authors.initials: J
authors.lastname: Dering
authors.forename: Lee
authors.initials: L
authors.lastname: Anderson
authors.forename: Charles
authors.initials: C
authors.lastname: Ginther
authors.forename: Alexandra
authors.initials: A
authors.lastname: Meuter
authors.forename: Boris
authors.initials: B
authors.lastname: Winterhoff
authors.forename: Siân
authors.initials: S
authors.lastname: Jones
authors.forename: Victor E
authors.initials: VE
authors.lastname: Velculescu
authors.forename: Natarajan
authors.initials: N
authors.lastname: Venkatesan
authors.forename: Hong-Mei
authors.initials: HM
authors.lastname: Rong
authors.forename: Sugandha
authors.initials: S
authors.lastname: Dandekar
authors.forename: Nitin
authors.initials: N
authors.lastname: Udar
authors.forename: Fritz
authors.initials: F
authors.lastname: Jänicke
authors.forename: Gerrit
authors.initials: G
authors.lastname: Los
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Slamon
authors.forename: Gottfried E
authors.initials: GE
authors.lastname: Konecny
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D024682:BRCA2 Protein / Q000235:genetics; D045744:Cell Line, Tumor; D053938:DNA Fragmentation / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D009154:Mutation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D019772:Topotecan / Q000008:administration & dosage; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
chemical_list: D024682:BRCA2 Protein; C551750:BRCA2 protein, human; C468783:H2AX protein, human; D006657:Histones; D007211:Indoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D019772:Topotecan; C531549:rucaparib; C111164:BRAP protein, human; D044767:Ubiquitin-Protein Ligases; D011065:Poly(ADP-ribose) Polymerases