[en] 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 NFkappaB 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.
Disciplines :
Life sciences: Multidisciplinary, general & others
Author, co-author :
Del Mistro, Greta
Lucarelli, Philippe ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Life Science Research Unit
Muller, Ines
De Landtsheer, Sébastien ; University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Zinoveva, Anna
Hutt, Meike
Siegemund, Martin
Kontermann, Roland E.
Beissert, Stefan
Sauter, Thomas ; University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Kulms, Dagmar
External co-authors :
yes
Language :
English
Title :
Systemic network analysis identifies XIAP and IkappaBalpha as potential drug targets in TRAIL resistant BRAF mutated melanoma.
Publication date :
November 2018
Journal title :
NPJ Systems Biology and Applications
ISSN :
2056-7189
Publisher :
Springer Nature
Volume :
4
Pages :
39
Peer reviewed :
Peer Reviewed verified by ORBi
European Projects :
H2020 - 642295 - MEL-PLEX - Exploiting MELanoma disease comPLEXity to address European research training needs in translational cancer systems biology and cancer systems medicine
FnR Project :
FNR7643621 - Predicting Individual Sensitivity Of Malignant Melanoma To Combination Therapies By Statistical And Network Modeling On Innovative 3d Organotypic Screening Models, 2013 (01/05/2015-30/04/2018) - Thomas Sauter