title: Small Cell Lung Cancer Screen of Oncology Drugs, Investigational Agents, and Gene and microRNA Expression.
abstract: Small cell lung carcinoma (SCLC) is an aggressive, recalcitrant cancer, often metastatic at diagnosis and unresponsive to chemotherapy upon recurrence, thus it is challenging to treat.
  
  
  
  Sixty-three human SCLC lines and three NSCLC lines were screened for response to 103 US Food and Drug Administration-approved oncology agents and 423 investigational agents. The investigational agents library was a diverse set of small molecules that included multiple compounds targeting the same molecular entity. The compounds were screened in triplicate at nine concentrations with a 96-hour exposure time using an ATP Lite endpoint. Gene expression was assessed by exon array, and microRNA expression was derived by direct digital detection. Activity across the SCLC lines was associated with molecular characteristics using pair-wise Pearson correlations.
  
  
  
  Results are presented for inhibitors of targets: BCL2, PARP1, mTOR, IGF1R, KSP/Eg5, PLK-1, AURK, and FGFR1. A relational map identified compounds with similar patterns of response. Unsupervised microRNA clustering resulted in three distinct SCLC subgroups. Associating drug response with micro-RNA expression indicated that lines most sensitive to etoposide and topotecan expressed high miR-200c-3p and low miR-140-5p and miR-9-5p. The BCL-2/BCL-XL inhibitors produced similar response patterns. Sensitivity to ABT-737 correlated with higher ASCL1 and BCL2. Several classes of compounds targeting nuclear proteins regulating mitosis produced a response pattern distinct from the etoposide response pattern.
  
  
  
  Agents targeting nuclear kinases appear to be effective in SCLC lines. Confirmation of SCLC line findings in xenografts is needed. The drug and compound response, gene expression, and microRNA expression data are publicly available at http://sclccelllines.cancer.gov.
authors.affiliation: Affiliations of authors: Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD (DE, TS, RD, JL, CO, RR, MS, JC, EH, NF, AM); Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis (MK, GK, JM, BAT), Biometric Research Program, Division of Cancer Treatment and Diagnosis (EP, DS), and Cancer Therapy Evaluation Program (SM), National Cancer Institute, Rockville, MD.
authors.forename: Eric
authors.initials: E
authors.lastname: Polley
authors.affiliation: Affiliations of authors: Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD (DE, TS, RD, JL, CO, RR, MS, JC, EH, NF, AM); Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis (MK, GK, JM, BAT), Biometric Research Program, Division of Cancer Treatment and Diagnosis (EP, DS), and Cancer Therapy Evaluation Program (SM), National Cancer Institute, Rockville, MD.
authors.forename: Mark
authors.initials: M
authors.lastname: Kunkel
authors.affiliation: Affiliations of authors: Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD (DE, TS, RD, JL, CO, RR, MS, JC, EH, NF, AM); Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis (MK, GK, JM, BAT), Biometric Research Program, Division of Cancer Treatment and Diagnosis (EP, DS), and Cancer Therapy Evaluation Program (SM), National Cancer Institute, Rockville, MD.
authors.forename: David
authors.initials: D
authors.lastname: Evans
authors.affiliation: Affiliations of authors: Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD (DE, TS, RD, JL, CO, RR, MS, JC, EH, NF, AM); Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis (MK, GK, JM, BAT), Biometric Research Program, Division of Cancer Treatment and Diagnosis (EP, DS), and Cancer Therapy Evaluation Program (SM), National Cancer Institute, Rockville, MD.
authors.forename: Thomas
authors.initials: T
authors.lastname: Silvers
authors.affiliation: Affiliations of authors: Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD (DE, TS, RD, JL, CO, RR, MS, JC, EH, NF, AM); Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis (MK, GK, JM, BAT), Biometric Research Program, Division of Cancer Treatment and Diagnosis (EP, DS), and Cancer Therapy Evaluation Program (SM), National Cancer Institute, Rockville, MD.
authors.forename: Rene
authors.initials: R
authors.lastname: Delosh
authors.affiliation: Affiliations of authors: Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD (DE, TS, RD, JL, CO, RR, MS, JC, EH, NF, AM); Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis (MK, GK, JM, BAT), Biometric Research Program, Division of Cancer Treatment and Diagnosis (EP, DS), and Cancer Therapy Evaluation Program (SM), National Cancer Institute, Rockville, MD.
authors.forename: Julie
authors.initials: J
authors.lastname: Laudeman
authors.affiliation: Affiliations of authors: Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD (DE, TS, RD, JL, CO, RR, MS, JC, EH, NF, AM); Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis (MK, GK, JM, BAT), Biometric Research Program, Division of Cancer Treatment and Diagnosis (EP, DS), and Cancer Therapy Evaluation Program (SM), National Cancer Institute, Rockville, MD.
authors.forename: Chad
authors.initials: C
authors.lastname: Ogle
authors.affiliation: Affiliations of authors: Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD (DE, TS, RD, JL, CO, RR, MS, JC, EH, NF, AM); Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis (MK, GK, JM, BAT), Biometric Research Program, Division of Cancer Treatment and Diagnosis (EP, DS), and Cancer Therapy Evaluation Program (SM), National Cancer Institute, Rockville, MD.
authors.forename: Russell
authors.initials: R
authors.lastname: Reinhart
authors.affiliation: Affiliations of authors: Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD (DE, TS, RD, JL, CO, RR, MS, JC, EH, NF, AM); Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis (MK, GK, JM, BAT), Biometric Research Program, Division of Cancer Treatment and Diagnosis (EP, DS), and Cancer Therapy Evaluation Program (SM), National Cancer Institute, Rockville, MD.
authors.forename: Michael
authors.initials: M
authors.lastname: Selby
authors.affiliation: Affiliations of authors: Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD (DE, TS, RD, JL, CO, RR, MS, JC, EH, NF, AM); Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis (MK, GK, JM, BAT), Biometric Research Program, Division of Cancer Treatment and Diagnosis (EP, DS), and Cancer Therapy Evaluation Program (SM), National Cancer Institute, Rockville, MD.
authors.forename: John
authors.initials: J
authors.lastname: Connelly
authors.affiliation: Affiliations of authors: Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD (DE, TS, RD, JL, CO, RR, MS, JC, EH, NF, AM); Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis (MK, GK, JM, BAT), Biometric Research Program, Division of Cancer Treatment and Diagnosis (EP, DS), and Cancer Therapy Evaluation Program (SM), National Cancer Institute, Rockville, MD.
authors.forename: Erik
authors.initials: E
authors.lastname: Harris
authors.affiliation: Affiliations of authors: Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD (DE, TS, RD, JL, CO, RR, MS, JC, EH, NF, AM); Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis (MK, GK, JM, BAT), Biometric Research Program, Division of Cancer Treatment and Diagnosis (EP, DS), and Cancer Therapy Evaluation Program (SM), National Cancer Institute, Rockville, MD.
authors.forename: Nicole
authors.initials: N
authors.lastname: Fer
authors.affiliation: Affiliations of authors: Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD (DE, TS, RD, JL, CO, RR, MS, JC, EH, NF, AM); Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis (MK, GK, JM, BAT), Biometric Research Program, Division of Cancer Treatment and Diagnosis (EP, DS), and Cancer Therapy Evaluation Program (SM), National Cancer Institute, Rockville, MD.
authors.forename: Dmitriy
authors.initials: D
authors.lastname: Sonkin
authors.affiliation: Affiliations of authors: Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD (DE, TS, RD, JL, CO, RR, MS, JC, EH, NF, AM); Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis (MK, GK, JM, BAT), Biometric Research Program, Division of Cancer Treatment and Diagnosis (EP, DS), and Cancer Therapy Evaluation Program (SM), National Cancer Institute, Rockville, MD.
authors.forename: Gurmeet
authors.initials: G
authors.lastname: Kaur
authors.affiliation: Affiliations of authors: Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD (DE, TS, RD, JL, CO, RR, MS, JC, EH, NF, AM); Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis (MK, GK, JM, BAT), Biometric Research Program, Division of Cancer Treatment and Diagnosis (EP, DS), and Cancer Therapy Evaluation Program (SM), National Cancer Institute, Rockville, MD.
authors.forename: Anne
authors.initials: A
authors.lastname: Monks
authors.affiliation: Affiliations of authors: Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD (DE, TS, RD, JL, CO, RR, MS, JC, EH, NF, AM); Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis (MK, GK, JM, BAT), Biometric Research Program, Division of Cancer Treatment and Diagnosis (EP, DS), and Cancer Therapy Evaluation Program (SM), National Cancer Institute, Rockville, MD.
authors.forename: Shakun
authors.initials: S
authors.lastname: Malik
authors.affiliation: Affiliations of authors: Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD (DE, TS, RD, JL, CO, RR, MS, JC, EH, NF, AM); Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis (MK, GK, JM, BAT), Biometric Research Program, Division of Cancer Treatment and Diagnosis (EP, DS), and Cancer Therapy Evaluation Program (SM), National Cancer Institute, Rockville, MD.
authors.forename: Joel
authors.initials: J
authors.lastname: Morris
authors.affiliation: Affiliations of authors: Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD (DE, TS, RD, JL, CO, RR, MS, JC, EH, NF, AM); Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis (MK, GK, JM, BAT), Biometric Research Program, Division of Cancer Treatment and Diagnosis (EP, DS), and Cancer Therapy Evaluation Program (SM), National Cancer Institute, Rockville, MD.
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Teicher
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001713:Biphenyl Compounds / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D015507:Drugs, Investigational / Q000627:therapeutic use*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics; D009596:Nitrophenols / Q000627:therapeutic use; D010879:Piperazines / Q000627:therapeutic use; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000037:antagonists & inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000037:antagonists & inhibitors; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000235:genetics*; D013449:Sulfonamides / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D000097869:Polo-Like Kinase 1
chemical_list: D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D018797:Cell Cycle Proteins; D015507:Drugs, Investigational; D016547:Kinesins; D035683:MicroRNAs; D009596:Nitrophenols; D010879:Piperazines; D000071137:Poly (ADP-Ribose) Polymerase-1; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin; D013449:Sulfonamides; D058570:TOR Serine-Threonine Kinases; D000097869:Polo-Like Kinase 1; C501332:ABT-737; C000595707:BCL2 protein, human; C000597236:IGF1R protein, human; C470243:KIF11 protein, human; C533896:MIRN200 microRNA, human; C541874:MIRN92 microRNA, human; C544302:Mirn140 microRNA, human; C499320:PARP1 protein, human; C546842:MTOR protein, human; C496348:FGFR1 protein, human