Reference : Focal adhesion kinase plays a dual role in TRAIL resistance and metastatic outgrowth ...
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
Systems Biomedicine
http://hdl.handle.net/10993/49786
Focal adhesion kinase plays a dual role in TRAIL resistance and metastatic outgrowth of malignant melanoma
English
Del Mistro, Greta [Experimental Dermatology, Department of Dermatology, TU-Dresden, 01307, Dresden, Germany]
Riemann, Shamala [Experimental Dermatology, Department of Dermatology, TU-Dresden, 01307, Dresden, Germany]
Schindler, Sebastian [Experimental Dermatology, Department of Dermatology, TU-Dresden, 01307, Dresden, Germany. > > > ; National Center for Tumor Diseases Dresden, TU-Dresden, 01307, Dresden, Germany.]
Beissert, Stefan [Experimental Dermatology, Department of Dermatology, TU-Dresden, 01307, Dresden, Germany]
Kontermann, Roland E [Institute of Cell Biology and Immunology and Stuttgart Research Centre Systems Biology, University of Stuttgart, 70569, Stuttgart, Germany]
Ginolhac, Aurélien mailto [University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM) >]
Halder, Rashi [Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, 4367, Luxembourg.]
Presta, Luana mailto [University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM) >]
Sinkkonen, Lasse mailto [University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM) >]
Sauter, Thomas mailto [University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM) >]
Kulms, Dagmar [Experimental Dermatology, Department of Dermatology, TU-Dresden, 01307, Dresden, Germany. > > > ; National Center for Tumor Diseases Dresden, TU-Dresden, 01307, Dresden, Germany.]
12-Jan-2022
Cell Death and Disease
Nature Publishing Group
Yes (verified by ORBilu)
International
2041-4889
London
United Kingdom
[en] Melanoma ; TRAIL-receptor ; Drug resistance
[en] Despite remarkable advances in therapeutic interventions, malignant melanoma (MM) remains a life-threating disease. Following high initial response rates to targeted kinase-inhibition metastases quickly acquire resistance and present with enhanced tumor progression and invasion, demanding alternative treatment options. We show 2nd generation hexameric TRAIL-receptor-agonist IZI1551 (IZI) to effectively induce apoptosis in MM cells irrespective of the intrinsic BRAF/NRAS mutation status. Conditioning to the EC50 dose of IZI converted the phenotype of IZI-sensitive parental MM cells into a fast proliferating and invasive, IZI-resistant metastasis. Mechanistically, we identified focal adhesion kinase (FAK) to play a dual role in phenotype-switching. In the cytosol, activated FAK triggers survival pathways in a PI3K- and MAPK-dependent manner. In the nucleus, the FERM domain of FAK prevents activation of wtp53, as being expressed in the majority of MM, and consequently intrinsic apoptosis. Caspase-8-mediated cleavage of FAK as well as FAK knockdown, and pharmacological inhibition, respectively, reverted the metastatic phenotype-switch and restored IZI responsiveness. FAK inhibition also re-sensitized MM cells isolated from patient metastasis that had relapsed from targeted kinase inhibition to cell death, irrespective of the intrinsic BRAF/NRAS mutation status. Hence, FAK-inhibition alone or in combination with 2nd generation TRAIL-receptor agonists may be recommended for treatment of initially resistant and relapsed MM, respectively.
University of Luxembourg: High Performance Computing - ULHPC
http://hdl.handle.net/10993/49786
10.1038/s41419-022-04502-8

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