Format

Send to

Choose Destination
NPJ Syst Biol Appl. 2018 Nov 5;4:39. doi: 10.1038/s41540-018-0075-y. eCollection 2018.

Systemic network analysis identifies XIAP and IκBα as potential drug targets in TRAIL resistant BRAF mutated melanoma.

Author information

1
1Experimental Dermatology, Department of Dermatology, TU-Dresden, Dresden, 01307 Germany.
2
2Center of Regenerative Therapies Dresden, TU-Dresden, Dresden, 01307 Germany.
3
3Systems Biology, Life Science Research Unit, University of Luxembourg, Belvaux, 4367 Luxembourg.
4
4Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, 70569 Germany.
5
5Stuttgart Research Center Systems Biology, University of Stuttgart, Stuttgart, 70569 Germany.
#
Contributed equally

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 NFκB 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.

Conflict of interest statement

R.E.K. is a consultant to Sunrock Biopharma (Santiago de Compostela) and Oncomatryx (Bilbao). M.H., M.S., and R.E.K. are named inventors on patent applications covering the scTRAIL technology. The remaining authors declare no competing interests.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center