The molecular mechanisms responsible for resistance to ET-743 (Trabectidin; Yondelis) in the Ewing's sarcoma cell line, TC-71

Int J Oncol. 2005 Dec;27(6):1605-16.


Identification of new active agents against sarcoma is considered an important challenge in medical oncology. ET-743 (Trabectidin; Yondelis) has recently emerged as the first active drug developed against sarcoma in the last two decades, with promising results especially against soft-tissue sarcoma and Ewing's sarcoma (ES). In this study, we analyzed the molecular mechanisms responsible for resistance to ET-743 in ES cells. Three resistant cell variants (TC/ET 3 nM, TC/ET 6 nM and TC/ET 12 nM) were obtained, showing 28-, 47- and 102-fold increase in ET-743 resistance. Cross-resistance to other drugs was analyzed. Comparative genomic hybridization and cDNA microarray technology were employed to characterize and compare the gene expression profile of two TC/ET variants with the parental cell line. TC/ET cells show a conventional multidrug resistance phenotype and P-glycoprotein overexpression was found to significantly contribute to ET-743 resistance. However, functional studies with the cyclosporine analogue, PSC-833, indicate that other mechanisms are involved in resistance to ET-743. The gene expression profile of TC/ET cells indicated, among up-regulated genes, an increase in expression of insulin-like growth factor receptor-I (IGF-IR) and one of its major intracellular mediators, insulin receptor substrate-1. Functional studies using a neutralizing antibody anti-IGF-IR confirmed involvement of this signaling pathway in resistance to ET-743. Simultaneous blockage of both P-glycoprotein and IGF-IR completely restored sensitivity to ET-743 in ES cells. Overall, these findings provide impetus for future studies testing the therapeutic value of new specific inhibitors of P-glycoprotein and IGF-IR, which could represent a concrete therapeutic option for ES patients refractory to conventional agents.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Antineoplastic Agents, Alkylating / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cyclosporins / pharmacology
  • Dioxoles / pharmacology*
  • Drug Resistance, Multiple / genetics
  • Drug Resistance, Neoplasm / genetics*
  • Flow Cytometry
  • Fluorescent Antibody Technique, Indirect
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / genetics
  • Genome, Human
  • Humans
  • Inhibitory Concentration 50
  • Isoquinolines / pharmacology*
  • Nucleic Acid Hybridization / methods
  • Oligonucleotide Array Sequence Analysis / methods
  • Receptor, IGF Type 1 / genetics
  • Sarcoma, Ewing / genetics
  • Sarcoma, Ewing / metabolism
  • Sarcoma, Ewing / pathology
  • Tetrahydroisoquinolines
  • Time Factors
  • Trabectedin


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antineoplastic Agents, Alkylating
  • Cyclosporins
  • Dioxoles
  • Isoquinolines
  • Tetrahydroisoquinolines
  • Receptor, IGF Type 1
  • Trabectedin
  • valspodar