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TRAIL-induced apoptosis is preferentially mediated via TRAIL receptor 1 in pancreatic carcinoma cells and profoundly enhanced by XIAP inhibitors.

AbstractPURPOSE:
We previously reported that small molecule X-linked inhibitor of apoptosis (XIAP) inhibitors synergize with soluble TRAIL to trigger apoptosis in pancreatic carcinoma cells. Because cancers may preferentially signal via 1 of the 2 agonistic TRAIL receptors, we investigated these receptors as a therapeutic target in pancreatic cancer in the present study.
EXPERIMENTAL DESIGN:
We examined TRAIL receptor expression and cytotoxicity of specific monoclonal antibodies to TRAIL-R1 (HGS-ETR1, mapatumumab) or TRAIL-R2 (HGS-ETR2, lexatumumab) and of TRAIL receptor selective mutants alone and in combination with small molecule XIAP inhibitors in pancreatic cancer cell lines, in primary specimens, and in a xenotransplant model in vivo.
RESULTS:
The majority of primary pancreatic carcinoma samples and all cell lines express one or both agonistic TRAIL receptors. Nine of 13 cell lines are more sensitive to mapatumumab-induced apoptosis, whereas lexatumumab requires cross-linking for maximal activity. Similarly, TRAIL-R1 selective mutants display higher cytotoxicity than TRAIL-R2 selective mutants. Small molecule XIAP inhibitors preferentially act in concert with mapatumumab to trigger caspase activation, caspase-dependent apoptosis, and suppress clonogenic survival. Also, primary cultured pancreatic carcinoma cells are more susceptible to mapatumumab than lexatumumab, which is significantly enhanced by a XIAP inhibitor. Importantly, combined treatment with mapatumumab and a XIAP inhibitor cooperates to suppress tumor growth in vivo.
CONCLUSIONS:
Mapatumumab exerts antitumor activity, especially in combination with XIAP inhibitors against most pancreatic carcinoma cell lines, whereas lexatumumab requires cross-linking for optimal cytotoxicity. These findings have important implications for the design of TRAIL-based protocols for pancreatic cancer.
AuthorsDominic Stadel, Andrea Mohr, Caroline Ref, Marion MacFarlane, Shaoxia Zhou, Robin Humphreys, Max Bachem, Gerry Cohen, Peter Möller, Ralf M Zwacka, Klaus-Michael Debatin, Simone Fulda
JournalClinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 16 Issue 23 Pg. 5734-49 (Dec 01 2010) ISSN: 1557-3265 [Electronic] United States
PMID20940278 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright©2010 AACR.
Chemical References
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • TNF-Related Apoptosis-Inducing Ligand
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human
  • mapatumumab
Topics
  • Aged
  • Animals
  • Antibodies, Monoclonal (administration & dosage, pharmacology)
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents (administration & dosage, pharmacology)
  • Apoptosis (drug effects)
  • Carcinoma (metabolism, pathology)
  • Cell Line, Tumor
  • Chick Embryo
  • Drug Evaluation, Preclinical
  • Drug Synergism
  • Female
  • Humans
  • Pancreatic Neoplasms (metabolism, pathology)
  • Receptors, TNF-Related Apoptosis-Inducing Ligand (agonists, metabolism, physiology)
  • TNF-Related Apoptosis-Inducing Ligand (administration & dosage, pharmacology)
  • X-Linked Inhibitor of Apoptosis Protein (antagonists & inhibitors)

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