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TRAIL-Induced Apoptosis Is Preferentially Mediated via TRAIL Receptor 1 in Pancreatic Carcinoma Cells and Profoundly Enhanced by XIAP Inhibitors

Stadel, Dominic and Mohr, Andrea and Ref, Caroline and MacFarlane, Marion and Zhou, Shaoxia and Humphreys, Robin and Bachem, Max and Cohen, Gerry and Möller, Peter and Zwacka, Ralf M and Debatin, Klaus-Michael and Fulda, Simone (2010) 'TRAIL-Induced Apoptosis Is Preferentially Mediated via TRAIL Receptor 1 in Pancreatic Carcinoma Cells and Profoundly Enhanced by XIAP Inhibitors.' Clinical Cancer Research, 16 (23). pp. 5734-5749. ISSN 1078-0432

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Abstract

<jats:title>Abstract</jats:title> <jats:p>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.</jats:p> <jats:p>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.</jats:p> <jats:p>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.</jats:p> <jats:p>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. Clin Cancer Res; 16(23); 5734–49. ©2010 AACR.</jats:p>

Item Type: Article
Uncontrolled Keywords: Cell Line, Tumor; Chick Embryo; Animals; Humans; Carcinoma; Pancreatic Neoplasms; Antineoplastic Agents; Antibodies, Monoclonal; Drug Evaluation, Preclinical; Apoptosis; Drug Synergism; Aged; Female; X-Linked Inhibitor of Apoptosis Protein; TNF-Related Apoptosis-Inducing Ligand; Receptors, TNF-Related Apoptosis-Inducing Ligand; Antibodies, Monoclonal, Humanized
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Divisions: Faculty of Science and Health
Faculty of Science and Health > Life Sciences, School of
SWORD Depositor: Elements
Depositing User: Elements
Date Deposited: 29 Nov 2013 12:34
Last Modified: 21 Jun 2022 02:46
URI: http://repository.essex.ac.uk/id/eprint/8319

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