title: PARP Inhibitor Activity Correlates with SLFN11 Expression and Demonstrates Synergy with Temozolomide in Small Cell Lung Cancer.
abstract: OBJECTIVE
  PARP inhibitors (PARPi) are a novel class of small molecule therapeutics for small cell lung cancer (SCLC). Identification of predictors of response would advance our understanding, and guide clinical application, of this therapeutic strategy.
  
  
  METHODS
  Efficacy of PARP inhibitors olaparib, rucaparib, and veliparib, as well as etoposide and cisplatin in SCLC cell lines, and gene expression correlates, was analyzed using public datasets. HRD genomic scar scores were calculated from Affymetrix SNP 6.0 arrays. In vitro talazoparib efficacy was measured by cell viability assays. For functional studies, CRISPR/Cas9 and shRNA were used for genomic editing and transcript knockdown, respectively. Protein levels were assessed by immunoblotting and immunohistochemistry (IHC). Quantitative synergy of talazoparib and temozolomide was determined in vitro In vivo efficacy of talazoparib, temozolomide, and the combination was assessed in patient-derived xenograft (PDX) models.
  
  
  RESULTS
  We identified SLFN11, but not HRD genomic scars, as a consistent correlate of response to all three PARPi assessed, with loss of SLFN11 conferring resistance to PARPi. We confirmed these findings in vivo across multiple PDX and defined IHC staining for SLFN11 as a predictor of talazoparib response. As temozolomide has activity in SCLC, we investigated combination therapy with talazoparib and found marked synergy in vitro and efficacy in vivo, which did not solely depend on SLFN11 or MGMT status.
  
  
  CONCLUSIONS
  SLFN11 is a relevant predictive biomarker of sensitivity to PARP inhibitor monotherapy in SCLC and we identify combinatorial therapy with TMZ as a particularly promising therapeutic strategy that warrants further clinical investigation. Clin Cancer Res; 23(2); 523-35. ©2016 AACR.
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.|Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Benjamin H
authors.initials: BH
authors.lastname: Lok
authors.affiliation: Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York.|Pharmacology Graduate Training Program, Department of Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Gardner
authors.affiliation: Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Valentina E
authors.initials: VE
authors.lastname: Schneeberger
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Andy
authors.initials: A
authors.lastname: Ni
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Patrice
authors.initials: P
authors.lastname: Desmeules
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Natasha
authors.initials: N
authors.lastname: Rekhtman
authors.affiliation: Anti-Tumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Elisa
authors.initials: E
authors.lastname: de Stanchina
authors.affiliation: Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland.
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Teicher
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Nadeem
authors.initials: N
authors.lastname: Riaz
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.|Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York.|Weill Cornell Medical College, New York, New York.
authors.forename: Simon N
authors.initials: SN
authors.lastname: Powell
authors.affiliation: Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York. rudinc@mskcc.org poirierj@mskcc.org.|Weill Cornell Medical College, New York, New York.|Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: John T
authors.initials: JT
authors.lastname: Poirier
authors.affiliation: Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York. rudinc@mskcc.org poirierj@mskcc.org.|Weill Cornell Medical College, New York, New York.|Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rudin
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D001562:Benzimidazoles / Q000008:administration & dosage; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004357:Drug Synergism; D005047:Etoposide / Q000008:administration & dosage; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D023281:Genomics / Q000379:methods; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics*; D010793:Phthalazines / Q000008:administration & dosage; D010879:Piperazines / Q000008:administration & dosage; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000037:antagonists & inhibitors / Q000235:genetics*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage*; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000077204:Temozolomide; D023041:Xenograft Model Antitumor Assays
chemical_list: D001562:Benzimidazoles; D007211:Indoles; D009687:Nuclear Proteins; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C576668:SLFN11 protein, human; C521013:veliparib; D005047:Etoposide; D003606:Dacarbazine; C531549:rucaparib; C586365:talazoparib; D000071137:Poly (ADP-Ribose) Polymerase-1; D002945:Cisplatin; C531550:olaparib; D000077204:Temozolomide