[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.
Research center :
ULHPC - University of Luxembourg: High Performance Computing
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
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 ; 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 ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
Sinkkonen, Lasse ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
Sauter, Thomas ; 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.
External co-authors :
yes
Language :
English
Title :
Focal adhesion kinase plays a dual role in TRAIL resistance and metastatic outgrowth of malignant melanoma