title: Loss of CUL4A expression is underlying cisplatin hypersensitivity in colorectal carcinoma cells with acquired trabectedin resistance.
abstract: BACKGROUND
  Colorectal carcinoma (CRC) is the third most common cancer worldwide. Platinum-based anticancer compounds still constitute one mainstay of systemic CRC treatment despite limitations due to adverse effects and resistance development. Trabectedin has shown promising antitumor effects in CRC, however, again resistance development may occur. In this study, we aimed to develop strategies to circumvent or even exploit acquired trabectedin resistance in novel CRC treatment regimens.
  
  
  METHODS
  Human HCT116 CRC cells were selected for acquired trabectedin resistance in vitro and characterised by cell biological as well as bioinformatic approaches. In vivo xenograft experiments were conducted.
  
  
  RESULTS
  Selection of HCT116 cells for trabectedin resistance resulted in p53-independent hypersensitivity of the selected subline against cisplatin. Bioinformatic analyses of mRNA microarray data suggested deregulation of nucleotide excision repair and particularly loss of the ubiquitin ligase CUL4A in trabectedin-selected cells. Indeed, transient knockdown of CUL4A sensitised parental HCT116 cells towards cisplatin. Trabectedin selected but not parental HCT116 xenografts were significantly responsive towards cisplatin treatment.
  
  
  CONCLUSIONS
  Trabectedin selection-mediated CUL4A loss generates an Achilles heel in CRC cancer cells enabling effective cisplatin treatment. Hence, inclusion of trabectedin in cisplatin-containing cancer treatment regimens might cause profound synergism based on reciprocal resistance prevention.
authors.affiliation: Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
authors.forename: B
authors.initials: B
authors.lastname: Englinger
authors.affiliation: Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Mair
authors.affiliation: Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
authors.forename: W
authors.initials: W
authors.lastname: Miklos
authors.affiliation: Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
authors.forename: C
authors.initials: C
authors.lastname: Pirker
authors.affiliation: Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
authors.forename: T
authors.initials: T
authors.lastname: Mohr
authors.affiliation: Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
authors.forename: S
authors.initials: S
authors.lastname: van Schoonhoven
authors.affiliation: Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
authors.forename: D
authors.initials: D
authors.lastname: Lötsch
authors.affiliation: Department of Environmental Geosciences, University of Vienna, Althanstraße 14, A-1090 Vienna, Austria.
authors.forename: W
authors.initials: W
authors.lastname: Körner
authors.affiliation: Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
authors.forename: F
authors.initials: F
authors.lastname: Ferk
authors.affiliation: Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
authors.forename: S
authors.initials: S
authors.lastname: Knasmüller
authors.affiliation: Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.|Research Platform 'Translational Cancer Therapy Research', University of Vienna and Medical University of Vienna, Waehringer Str. 42, A-1090 Vienna, Austria.
authors.forename: P
authors.initials: P
authors.lastname: Heffeter
authors.affiliation: Research Platform 'Translational Cancer Therapy Research', University of Vienna and Medical University of Vienna, Waehringer Str. 42, A-1090 Vienna, Austria.|Institute of Inorganic Chemistry, University of Vienna, Waehringer Str. 42, A-1090 Vienna, Austria.
authors.forename: B K
authors.initials: BK
authors.lastname: Keppler
authors.affiliation: Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Grusch
authors.affiliation: Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.|Research Platform 'Translational Cancer Therapy Research', University of Vienna and Medical University of Vienna, Waehringer Str. 42, A-1090 Vienna, Austria.
authors.forename: W
authors.initials: W
authors.lastname: Berger
mesh_terms: D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics; D044842:Cullin Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics; D004149:Dioxoles / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D016158:Genes, p53; D045325:HCT116 Cells; D006801:Humans; D034741:RNA, Small Interfering / Q000494:pharmacology; D044005:Tetrahydroisoquinolines / Q000627:therapeutic use*; D000077606:Trabectedin
chemical_list: C114234:CUL4A protein, human; D044842:Cullin Proteins; D004149:Dioxoles; D034741:RNA, Small Interfering; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin; D002945:Cisplatin