| Literature DB >> 25043603 |
Jonathan D Graves1, Jennifer J Kordich1, Tzu-Hsuan Huang2, Julia Piasecki3, Tammy L Bush2, Timothy Sullivan2, Ian N Foltz4, Wesley Chang5, Heather Douangpanya1, Thu Dang2, Jason W O'Neill6, Rommel Mallari7, Xiaoning Zhao7, Daniel G Branstetter8, John M Rossi9, Alexander M Long10, Xin Huang10, Pamela M Holland11.
Abstract
Death receptor agonist therapies have exhibited limited clinical benefit to date. Investigations into why Apo2L/TRAIL and AMG 655 preclinical data were not predictive of clinical response revealed that coadministration of Apo2L/TRAIL with AMG 655 leads to increased antitumor activity in vitro and in vivo. The combination of Apo2L/TRAIL and AMG 655 results in enhanced signaling and can sensitize Apo2L/TRAIL-resistant cells. Structure determination of the Apo2L/TRAIL-DR5-AMG 655 ternary complex illustrates how higher order clustering of DR5 is achieved when both agents are combined. Enhanced agonism generated by combining Apo2L/TRAIL and AMG 655 provides insight into the limited efficacy observed in previous clinical trials and suggests testable hypotheses to reconsider death receptor agonism as a therapeutic strategy.Entities:
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Year: 2014 PMID： 25043603 DOI： 10.1016/j.ccr.2014.04.028
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743