Transcriptional signature of Ecteinascidin 743 (Yondelis, Trabectedin) in human sarcoma cells explanted from chemo-naive patients.
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.
Martínez
Nerea
N
Molecular Pathology Programme, Centro Nacional de Investigaciones Oncológicas, C/ Melchor Fernández Almagro 3, E-28029 Madrid, Spain.
Sánchez-Beato
Margarita
M
Carnero
Amancio
A
Moneo
Victoria
V
Tercero
Juan C
JC
Fernández
Isabel
I
Navarrete
Mercedes
M
Jimeno
José
J
Piris
Miguel A
MA
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
D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D016159:Tumor Suppressor Protein p53; D000077606:Trabectedin