TY  - JOUR
A1  - Rudelius, Martina
A1  - Rosenfeldt, Mathias Tillmann
A1  - Leich, Ellen
A1  - Rauert-Wunderlich, Hilka
A1  - Solimando, Antonio Giovanni
A1  - Ott, German
A1  - Rosenwald, Andreas
A1  - Beilhack, Andreas
T1  - Inhibition of focal adhesion kinase overcomes resistance of mantle cell lymphoma to ibrutinib in the bone marrow microenvironment
JF  - Haematologica
N2  - Mantle cell lymphoma and other lymphoma subtypes often spread to the bone marrow, and stromal interactions mediated by focal adhesion kinase frequently enhance survival and drug resistance of the lymphoma cells. To study the role of focal adhesion kinase in mantle cell lymphoma, immunohistochemistry of primary cases and functional analysis of mantle cell lymphoma cell lines and primary mantle cell lymphoma cells co-cultured with bone marrow stromal cells (BMSC) using small molecule inhibitors and RNAi-based focal adhesion kinase silencing was performed. We showed that focal adhesion kinase is highly expressed in bone marrow infiltrates of mantle cell lymphoma and in mantle cell lymphoma cell lines. Stroma-mediated activation of focal adhesion kinase led to activation of multiple kinases (AKT, p42/44 and NF-kappa B), that are important for prosurvival and proliferation signaling. Interestingly, RNAi-based focal adhesion kinase silencing or inhibition with small molecule inhibitors (FAKi) resulted in blockage of targeted cell invasion and induced apoptosis by inactivation of multiple signaling cascades, including the classic and alternative NF-kappa B pathway. In addition, the combined treatment of ibrutinib and FAKi was highly synergistic, and ibrutinib resistance of mantle cell lymphoma could be overcome. These data demonstrate that focal adhesion kinase is important for stroma-mediated survival and drug resistance in mantle cell lymphoma, providing indications for a targeted therapeutic strategy.
KW  - NF-Kappa-B
KW  - Stromal cells
KW  - Induced apoptosis
KW  - Fak regulation
KW  - Phase-
KW  - Multiple
KW  - Activation
KW  - Mechanisms
KW  - Migration
KW  - Pathogenesis
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227117
VL  - 103
IS  - 1
ER  - 
TY  - JOUR
A1  - Rauert-Wunderlich, Hilka
A1  - Berberich, Ingolf
A1  - Rosenwald, Andreas
A1  - Rudelius, Martina
T1  - CD40L mediated alternative NF kappa B-signaling induces resistance to BCR-inhibitors in patients with mantle cell lymphoma
JF  - Cell Death & Disease
N2  - Drug resistance is a significant obstacle in cancer treatment and therefore a frequent subject of research. Developed or primary resistance limits the treatment success of inhibitors of the B cell receptor (BCR) pathway in mantle cell lymphoma (MCL) patients. Recent research has highlighted the role of the nuclear factor-kappa B (NF kappa B) pathway in the context of resistance to BCR inhibitors in MCL. In this study, we analyzed the dependency of MCL cell lines on NF kappa B signaling and illustrated the ability of CD40L to activate the alternative NF kappa B pathway in MCL. This activation leads to independency of classical NF kappa B signaling and results in resistance to BCR inhibitors. Therefore, ligands (such as CD40L) and their activation of the alternative NF kappa B pathway have a major impact on the drug response in MCL. Furthermore, this study indicates a protective role for cells expressing specific ligands as microenvironmental niches for MCL cells and underlines the significance of therapeutically targeting alternative NF kappa B signaling in MCL.
KW  - Bruton Tyrosine Kinase
KW  - Tumor Microenvironment
KW  - Targeted Therapies
KW  - Ibrutinib
KW  - Pathway
KW  - Malignancies
KW  - Activation
KW  - Ligand
KW  - Proliferation
KW  - PCI-32765
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225027
IS  - 9
ER  -