兴奋剂
受体
体内
药理学
体外
痛苦
医学
化学
生物
内科学
生物化学
生物技术
政治
政治学
法学
作者
Jonathan D. Graves,Jennifer J. Kordich,Tzu-Hsuan Huang,Julia Piasecki,Tammy L. Bush,Timothy J. Sullivan,Ian N. Foltz,Wesley Chang,Heather Douangpanya,Thu Thi Dang,Jason O’Neill,Rommel Mallari,Xiaoning Zhao,Daniel Branstetter,John M. Rossi,Alexander Long,Xin Huang,Pamela M. Holland
出处
期刊:Cancer Cell
[Elsevier]
日期:2014-08-01
卷期号:26 (2): 177-189
被引量:137
标识
DOI:10.1016/j.ccr.2014.04.028
摘要
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.
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