title: Targeting the ATR/CHK1 Axis with PARP Inhibition Results in Tumor Regression inBRCA-Mutant Ovarian Cancer Models.
abstract: Purpose:PARP inhibition (PARPi) has modest clinical activity in recurrentBRCA-mutant (BRCAMUT) high-grade serous ovarian cancers (HGSOC). We hypothesized that PARPi increases dependence on ATR/CHK1 such that combination PARPi with ATR/CHK1 blockade results in increased cell death and tumor regression.Experimental Design:Effects of PARPi (olaparib), CHK1 inhibition (CHK1i;MK8776), or ATR inhibition (ATRi;AZD6738) alone or in combination on survival, colony formation, cell cycle, genome instability, and apoptosis were evaluated inBRCA1/2MUTHGSOC cells. Tumor growthin vivowas evaluated using aBRCA2MUTpatient-derived xenograft (PDX) model.Results:PARPi monotherapy resulted in a decrease inBRCAMUTcell survival, colony formation and suppressed but did not eliminate tumor growth at the maximum tolerated dose (MTD) in aBRCA2MUTPDX. PARPi treatment increased pATR and pCHK1, indicating activation of the ATR-CHK1 fork protection pathway is relied upon for genome stability under PARPi. Indeed, combination of ATRi or CHK1i with PARPi synergistically decreased survival and colony formation compared with single-agent treatments inBRCAMUTcells. Notably, PARPi led to G2phase accumulation, and the addition of ATRi or CHK1i released cells from G2causing premature mitotic entry with increased chromosomal aberrations and apoptosis. Moreover, the combinations of PARPi with ATRi or CHK1i were synergistic in causing tumor suppression in aBRCA2MUTPDX with the PARPi-ATRi combination inducing tumor regression and in most cases, complete remission.Conclusions:PARPi causes increased reliance on ATR/CHK1 for genome stability, and combination PARPi with ATR/CHK1i is more effective than PARPi alone in reducing tumor burden inBRCAMUTmodels.Clin Cancer Res; 23(12); 3097-108. ©2016 AACR.
authors.affiliation: Penn Ovarian Cancer Research Center, Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, University of Pennsylvania, Philadelphia, PA.
authors.forename: Hyoung
authors.initials: H
authors.lastname: Kim
authors.affiliation: Penn Ovarian Cancer Research Center, Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, University of Pennsylvania, Philadelphia, PA.
authors.forename: Erin
authors.initials: E
authors.lastname: George
authors.affiliation: Cancer Biology, University of Pennsylvania, Philadelphia, PA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Ragland
authors.affiliation: Penn Ovarian Cancer Research Center, Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, University of Pennsylvania, Philadelphia, PA.
authors.forename: Stavros
authors.initials: S
authors.lastname: Rafail
authors.affiliation: Wistar Institute, Philadelphia, PA.
authors.forename: Rugang
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Wistar Institute, Philadelphia, PA.
authors.forename: Clemens
authors.initials: C
authors.lastname: Krepler
authors.affiliation: Penn Ovarian Cancer Research Center, Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, University of Pennsylvania, Philadelphia, PA.
authors.forename: Mark
authors.initials: M
authors.lastname: Morgan
authors.affiliation: Wistar Institute, Philadelphia, PA.
authors.forename: Meenhard
authors.initials: M
authors.lastname: Herlyn
authors.affiliation: Cancer Biology, University of Pennsylvania, Philadelphia, PA.
authors.forename: Eric
authors.initials: E
authors.lastname: Brown
authors.affiliation: Penn Ovarian Cancer Research Center, Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, University of Pennsylvania, Philadelphia, PA.
authors.forename: Fiona
authors.initials: F
authors.lastname: Simpkins
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors; D019313:BRCA1 Protein / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000071877:Checkpoint Kinase 1 / Q000037:antagonists & inhibitors*; D004357:Drug Synergism; D005260:Female; D042822:Genomic Instability / Q000187:drug effects; D006801:Humans; D007211:Indoles; D051379:Mice; D058990:Molecular Targeted Therapy; D009025:Morpholines; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010793:Phthalazines / Q000008:administration & dosage; D010879:Piperazines / Q000008:administration & dosage; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage; D011720:Pyrazoles / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D013449:Sulfonamides; D013454:Sulfoxides / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D007211:Indoles; C559815:MK-8776; D009025:Morpholines; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D013449:Sulfonamides; D013454:Sulfoxides; C000611951:ceralasertib; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C531550:olaparib