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Integrative analysis of kinase networks in TRAIL-induced apoptosis provides a source of potential targets for combination therapy

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Science Signaling  07 Apr 2015:
Vol. 8, Issue 371, pp. rs3
DOI: 10.1126/scisignal.2005700

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Networking death signals

Selective killing of cancer cells without the induction of resistance is the holy grail of cancer therapy. TRAIL is an endogenous secreted protein that promotes cell death, and cancer cells are particularly sensitive to this molecule. Unfortunately, some cancer cells evade TRAIL-induced death and develop resistance by rewiring their signaling networks. So et al. took a proteomic approach aimed at kinases, which are key regulators of cell survival and death, and mapped a protein interaction network encompassing kinases that they identified as affecting TRAIL-induced cell death. Modeling information flow through the network revealed potential targets that could be exploited to develop combination therapies with TRAIL to kill cancer cells and prevent resistance.


Tumor necrosis factor–related apoptosis–inducing ligand (TRAIL) is an endogenous secreted peptide and, in preclinical studies, preferentially induces apoptosis in tumor cells rather than in normal cells. The acquisition of resistance in cells exposed to TRAIL or its mimics limits their clinical efficacy. Because kinases are intimately involved in the regulation of apoptosis, we systematically characterized kinases involved in TRAIL signaling. Using RNA interference (RNAi) loss-of-function and cDNA overexpression screens, we identified 169 protein kinases that influenced the dynamics of TRAIL-induced apoptosis in the colon adenocarcinoma cell line DLD-1. We classified the kinases as sensitizers or resistors or modulators, depending on the effect that knockdown and overexpression had on TRAIL-induced apoptosis. Two of these kinases that were classified as resistors were PX domain–containing serine/threonine kinase (PXK) and AP2-associated kinase 1 (AAK1), which promote receptor endocytosis and may enable cells to resist TRAIL-induced apoptosis by enhancing endocytosis of the TRAIL receptors. We assembled protein interaction maps using mass spectrometry–based protein interaction analysis and quantitative phosphoproteomics. With these protein interaction maps, we modeled information flow through the networks and identified apoptosis-modifying kinases that are highly connected to regulated substrates downstream of TRAIL. The results of this analysis provide a resource of potential targets for the development of TRAIL combination therapies to selectively kill cancer cells.

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