Abstract | PURPOSE: 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.
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Authors | Dominic 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 |
Journal | Clinical 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 |
PMID | 20940278
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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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
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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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