title: Transcriptional signature of Ecteinascidin 743 (Yondelis, Trabectedin) in human sarcoma cells explanted from chemo-naive patients.
abstract: Ecteinascidin 743 (ET-743; Yondelis, Trabectedin) is a marine anticancer agent that induces long-lasting objective remissions and tumor control in a subset of patients with pretreated/resistant soft-tissue sarcoma. Drug-induced tumor control is achievable in 22% of such patients, but there is no clear indication of the molecular features correlated with clinical sensitivity/resistance to ET-743. Nine low-passage, soft-tissue sarcoma cell lines, explanted from chemo-naive patients with different patterns of sensitivity, have been profiled with a cDNA microarray containing 6,700 cancer-related genes. The molecular signature of these cell lines was analyzed at baseline and at four different times after ET-743 exposure. The association of levels of TP53 mutation and TP73 expression with ET-743 sensitivity and cell cycle kinetics after treatment was also analyzed. Gene expression profile analysis revealed up-regulation of 86 genes and down-regulation of 244 genes in response to ET-743. The ET-743 gene expression signature identified a group of genes related with cell cycle control, stress, and DNA-damage response (JUNB, ATF3, CS-1, SAT, GADD45B, and ID2) that were up-regulated in all the cell lines studied. The transcriptional signature 72 hours after ET-743 administration, associated with ET-743 sensitivity, showed a more efficient induction of genes involved in DNA-damage response and apoptosis, such as RAD17, BRCA1, PAR4, CDKN1A, and P53DINP1, in the sensitive cell line group. The transcriptional signature described here may lead to the identification of ET-743 downstream mediators and transcription regulators and the proposal of strategies by which ET-743-sensitive tumors may be identified.
authors.affiliation: Molecular Pathology Programme, Centro Nacional de Investigaciones Oncológicas, C/ Melchor Fernández Almagro 3, E-28029 Madrid, Spain.
authors.forename: Nerea
authors.initials: N
authors.lastname: Martínez
authors.forename: Margarita
authors.initials: M
authors.lastname: Sánchez-Beato
authors.forename: Amancio
authors.initials: A
authors.lastname: Carnero
authors.forename: Victoria
authors.initials: V
authors.lastname: Moneo
authors.forename: Juan C
authors.initials: JC
authors.lastname: Tercero
authors.forename: Isabel
authors.initials: I
authors.lastname: Fernández
authors.forename: Mercedes
authors.initials: M
authors.lastname: Navarrete
authors.forename: José
authors.initials: J
authors.lastname: Jimeno
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Piris
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D002453:Cell Cycle; D004149:Dioxoles / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D007700:Kinetics; D009154:Mutation / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D012509:Sarcoma / Q000235:genetics / Q000378:metabolism*; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D016159:Tumor Suppressor Protein p53; D000077606:Trabectedin