Metastatic melanoma remains a life-threatening disease because most tumors develop resistance to targeted kinase inhibitors thereby regaining tumorigenic capacity. We show the 2nd generation hexavalent TRAIL receptor-targeted agonist IZI1551 to induce pronounced apoptotic cell death in mutBRAF melanoma cells. Aiming to identify molecular changes that may confer IZI1551 resistance we combined Dynamic Bayesian Network modelling with a sophisticated regularization strategy resulting in sparse and context-sensitive networks and show the performance of this strategy in the detection of cell line-specific deregulations of a signalling network. Comparing IZI1551-sensitive to IZI1551-resistant melanoma cells the model accurately and correctly predicted activation of NF$\kappa$B in concert with upregulation of the anti-apoptotic protein XIAP as the key mediator of IZI1551 resistance. Thus, the incorporation of multiple regularization functions in logical network optimization may provide a promising avenue to assess the effects of drug combinations and to identify responders to selected combination therapies.
%0 Journal Article
%1 DelMistro2018
%A Del Mistro, Greta
%A Lucarelli, Philippe
%A Müller, Ines
%A De Landtsheer, Sébastien
%A Zinoveva, Anna
%A Hutt, Meike
%A Siegemund, Martin
%A Kontermann, Roland E.
%A Beissert, Stefan
%A Sauter, Thomas
%A Kulms, Dagmar
%D 2018
%J npj Systems Biology and Applications
%K 2018 izi kontermann
%N 1
%P 39
%R 10.1038/s41540-018-0075-y
%T Systemic network analysis identifies XIAP and IκBα as potential drug targets in TRAIL resistant BRAF mutated melanoma
%U http://www.ncbi.nlm.nih.gov/pubmed/30416750
%V 4
%X Metastatic melanoma remains a life-threatening disease because most tumors develop resistance to targeted kinase inhibitors thereby regaining tumorigenic capacity. We show the 2nd generation hexavalent TRAIL receptor-targeted agonist IZI1551 to induce pronounced apoptotic cell death in mutBRAF melanoma cells. Aiming to identify molecular changes that may confer IZI1551 resistance we combined Dynamic Bayesian Network modelling with a sophisticated regularization strategy resulting in sparse and context-sensitive networks and show the performance of this strategy in the detection of cell line-specific deregulations of a signalling network. Comparing IZI1551-sensitive to IZI1551-resistant melanoma cells the model accurately and correctly predicted activation of NF$\kappa$B in concert with upregulation of the anti-apoptotic protein XIAP as the key mediator of IZI1551 resistance. Thus, the incorporation of multiple regularization functions in logical network optimization may provide a promising avenue to assess the effects of drug combinations and to identify responders to selected combination therapies.
@article{DelMistro2018,
abstract = {Metastatic melanoma remains a life-threatening disease because most tumors develop resistance to targeted kinase inhibitors thereby regaining tumorigenic capacity. We show the 2nd generation hexavalent TRAIL receptor-targeted agonist IZI1551 to induce pronounced apoptotic cell death in mutBRAF melanoma cells. Aiming to identify molecular changes that may confer IZI1551 resistance we combined Dynamic Bayesian Network modelling with a sophisticated regularization strategy resulting in sparse and context-sensitive networks and show the performance of this strategy in the detection of cell line-specific deregulations of a signalling network. Comparing IZI1551-sensitive to IZI1551-resistant melanoma cells the model accurately and correctly predicted activation of NF$\kappa$B in concert with upregulation of the anti-apoptotic protein XIAP as the key mediator of IZI1551 resistance. Thus, the incorporation of multiple regularization functions in logical network optimization may provide a promising avenue to assess the effects of drug combinations and to identify responders to selected combination therapies.},
added-at = {2018-11-19T10:41:36.000+0100},
author = {{Del Mistro}, Greta and Lucarelli, Philippe and M{\"{u}}ller, Ines and {De Landtsheer}, S{\'{e}}bastien and Zinoveva, Anna and Hutt, Meike and Siegemund, Martin and Kontermann, Roland E. and Beissert, Stefan and Sauter, Thomas and Kulms, Dagmar},
biburl = {https://puma.ub.uni-stuttgart.de/bibtex/2f668387a4bcce4be985c5df9ef17deb8/cristiano},
doi = {10.1038/s41540-018-0075-y},
interhash = {4afee5e122ab7a6c5f0643fd7e496c1e},
intrahash = {f668387a4bcce4be985c5df9ef17deb8},
issn = {2056-7189},
journal = {npj Systems Biology and Applications},
keywords = {2018 izi kontermann},
month = dec,
number = 1,
pages = 39,
pmid = {30416750},
timestamp = {2019-01-17T12:16:37.000+0100},
title = {{Systemic network analysis identifies XIAP and IκBα as potential drug targets in TRAIL resistant BRAF mutated melanoma}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/30416750},
volume = 4,
year = 2018
}