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Data-driven Modeling of Kinase Networks in TRAIL-induced Apoptosis Inform Combination Therapy

Jonathan So

出版	University of Toronto, 2013
URL	http://books.google.com.hk/books?id=_dfmtwEACAAJ&hl=&source=gbs_api

註釋

Tumor-necrosis factor Related Apoptosis Inducing Ligand (TRAIL) is a soluble peptide that preferentially induces apoptosis in many solid tumors. Unfortunately, the emergence of resistance in treated cells limits the efficacy of TRAIL or other synthetic receptor agonists as single agent therapeutics. Since adaptation of the underlying signalling network may drive this resistance, we undertook a detailed characterisation of the cellular response to TRAIL to identify compensatory signaling nodes that could serve as candidates for combination therapy. As kinases are intimately linked with the regulation of apoptosis, we systematically evaluated the human kinome in the context of TRAIL-induced apoptosis through RNAi and over-expression screens, protein interaction mapping, and phospho-proteomics in the colon adenocarcinoma cell line DLD-1. We identified 164 kinases that influence TRAIL signaling, mapped out an underlying protein interaction network connecting these kinases to apoptotic regulators, and characterized two kinases (PXK, AAK1) that affect TRAIL sensitivity through modulating receptor endocytosis. Finally, by modeling changes in information flow through the signaling network, we identified novel combinations of kinases whose inhibition act synergistically to augment TRAIL-induced apoptosis.