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dc.contributor.authorStadel, D.
dc.contributor.authorMohr, A.
dc.contributor.authorRef, C.
dc.contributor.authorMacFarlane, M.
dc.contributor.authorZhou, S.
dc.contributor.authorHumphreys, R.
dc.contributor.authorBachem, M.
dc.contributor.authorCohen, G.
dc.contributor.authorMoller, P.
dc.contributor.authorZwacka, R. M.
dc.contributor.authorDebatin, K.-M.
dc.contributor.authorFulda, S.
dc.identifier.citationStadel, D. Mohr, A.; Ref, C.; MacFarlane, M.; Zhou, S.; Humphreys, R.; Bachem, M.; Cohen, G.; Moller, P.; Zwacka, R. M.; Debatin, K.-M.; Fulda, S. (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), 5734-5749
dc.description.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. Clin Cancer Res; 16(23); 5734-49. (C)2010 AACR.
dc.publisherAmerican Association for Cancer Research (AACR)
dc.relation.ispartofClinical Cancer Research
dc.rightsAttribution-NonCommercial-NoDerivs 3.0 Ireland
dc.subjectagonistic monoclonal-antibody
dc.subjectgrowth in-vivo
dc.subjectselective mutants
dc.titleTrail-induced apoptosis is preferentially mediated via trail receptor 1 in pancreatic carcinoma cells and profoundly enhanced by xiap inhibitors

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