title: Screening of Conditionally Reprogrammed Patient-Derived Carcinoma Cells Identifies ERCC3-MYC Interactions as a Target in Pancreatic Cancer.
abstract: OBJECTIVE
  Even when diagnosed prior to metastasis, pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy with almost 90% lethality, emphasizing the need for new therapies optimally targeting the tumors of individual patients.
  
  
  METHODS
  We first developed a panel of new physiologic models for study of PDAC, expanding surgical PDAC tumor samples in culture using short-term culture and conditional reprogramming with the Rho kinase inhibitor Y-27632, and creating matched patient-derived xenografts (PDX). These were evaluated for sensitivity to a large panel of clinical agents, and promising leads further evaluated mechanistically.
  
  
  RESULTS
  Only a small minority of tested agents was cytotoxic in minimally passaged PDAC cultures in vitro Drugs interfering with protein turnover and transcription were among most cytotoxic. Among transcriptional repressors, triptolide, a covalent inhibitor of ERCC3, was most consistently effective in vitro and in vivo causing prolonged complete regression in multiple PDX models resistant to standard PDAC therapies. Importantly, triptolide showed superior activity in MYC-amplified PDX models and elicited rapid and profound depletion of the oncoprotein MYC, a transcriptional regulator. Expression of ERCC3 and MYC was interdependent in PDACs, and acquired resistance to triptolide depended on elevated ERCC3 and MYC expression. The Cancer Genome Atlas analysis indicates ERCC3 expression predicts poor prognosis, particularly in CDKN2A-null, highly proliferative tumors.
  
  
  CONCLUSIONS
  This provides initial preclinical evidence for an essential role of MYC-ERCC3 interactions in PDAC, and suggests a new mechanistic approach for disruption of critical survival signaling in MYC-dependent cancers. Clin Cancer Res; 22(24); 6153-63. ©2016 AACR.
authors.affiliation: Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Natalya
authors.initials: N
authors.lastname: Beglyarova
authors.affiliation: Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Banina
authors.affiliation: Biostatistics and Bioinformatics Facility, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Biochemistry, Kazan Federal University, Kazan, Russian Federation.
authors.forename: Ramilia
authors.initials: R
authors.lastname: Mukhamadeeva
authors.affiliation: Department of Biochemistry, Kazan Federal University, Kazan, Russian Federation.
authors.forename: Grigorii
authors.initials: G
authors.lastname: Andrianov
authors.affiliation: Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Egor
authors.initials: E
authors.lastname: Bobrov
authors.affiliation: Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Elena
authors.initials: E
authors.lastname: Lysenko
authors.affiliation: Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Natalya
authors.initials: N
authors.lastname: Skobeleva
authors.affiliation: Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Linara
authors.initials: L
authors.lastname: Gabitova
authors.affiliation: Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Diana
authors.initials: D
authors.lastname: Restifo
authors.affiliation: Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Max
authors.initials: M
authors.lastname: Pressman
authors.affiliation: Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Ilya G
authors.initials: IG
authors.lastname: Serebriiskii
authors.affiliation: Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: John P
authors.initials: JP
authors.lastname: Hoffman
authors.affiliation: Champions Oncology, Baltimore, Maryland.
authors.forename: Keren
authors.initials: K
authors.lastname: Paz
authors.affiliation: EPO Experimental Pharmacology and Oncology GmbH, Berlin, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Behrens
authors.affiliation: Nexus Pharma, Langhorne, Pennsylvania.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Khazak
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
authors.forename: Sandra A
authors.initials: SA
authors.lastname: Jablonski
authors.affiliation: Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Erica A
authors.initials: EA
authors.lastname: Golemis
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
authors.forename: Louis M
authors.initials: LM
authors.lastname: Weiner
authors.affiliation: Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania. igor.astsaturov@fccc.edu.
authors.forename: Igor
authors.initials: I
authors.lastname: Astsaturov
mesh_terms: D000577:Amides / Q000494:pharmacology; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004265:DNA Helicases / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004224:Diterpenes / Q000494:pharmacology; D004852:Epoxy Compounds / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D064593:Heterografts / Q000378:metabolism; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D041681:NIH 3T3 Cells; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D010616:Phenanthrenes / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D000577:Amides; D004268:DNA-Binding Proteins; D004224:Diterpenes; D004852:Epoxy Compounds; D010616:Phenanthrenes; D016271:Proto-Oncogene Proteins c-myc; D011725:Pyridines; C108830:Y 27632; C072022:XPBC-ERCC-3 protein; C001899:triptolide; D054460:rho-Associated Kinases; D004265:DNA Helicases