TY  - JOUR
A1  - Munawar, Umair
A1  - Zhou, Xiang
A1  - Prommersberger, Sabrina
A1  - Nerreter, Silvia
A1  - Vogt, Cornelia
A1  - Steinhardt, Maximilian J.
A1  - Truger, Marietta
A1  - Mersi, Julia
A1  - Teufel, Eva
A1  - Han, Seungbin
A1  - Haertle, Larissa
A1  - Banholzer, Nicole
A1  - Eiring, Patrick
A1  - Danhof, Sophia
A1  - Navarro-Aguadero, Miguel Angel
A1  - Fernandez-Martin, Adrian
A1  - Ortiz-Ruiz, Alejandra
A1  - Barrio, Santiago
A1  - Gallardo, Miguel
A1  - Valeri, Antonio
A1  - Castellano, Eva
A1  - Raab, Peter
A1  - Rudert, Maximilian
A1  - Haferlach, Claudia
A1  - Sauer, Markus
A1  - Hudecek, Michael
A1  - Martinez-Lopez, J.
A1  - Waldschmidt, Johannes
A1  - Einsele, Hermann
A1  - Rasche, Leo
A1  - Kortüm, K. Martin
T1  - Impaired FADD/BID signaling mediates cross-resistance to immunotherapy in Multiple Myeloma
JF  - Communications Biology
N2  - The treatment landscape in multiple myeloma (MM) is shifting from genotoxic drugs to immunotherapies. Monoclonal antibodies, immunoconjugates, T-cell engaging antibodies and CART cells have been incorporated into routine treatment algorithms, resulting in improved response rates. Nevertheless, patients continue to relapse and the underlying mechanisms of resistance remain poorly understood. While Impaired death receptor signaling has been reported to mediate resistance to CART in acute lymphoblastic leukemia, this mechanism yet remains to be elucidated in context of novel immunotherapies for MM. Here, we describe impaired death receptor signaling as a novel mechanism of resistance to T-cell mediated immunotherapies in MM. This resistance seems exclusive to novel immunotherapies while sensitivity to conventional anti-tumor therapies being preserved in vitro. As a proof of concept, we present a confirmatory clinical case indicating that the FADD/BID axis is required for meaningful responses to novel immunotherapies thus we report impaired death receptor signaling as a novel resistance mechanism to T-cell mediated immunotherapy in MM.
KW  - immunotherapy
KW  - translational research
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357609
VL  - 6
ER  - 
TY  - JOUR
A1  - Garitano-Trojaola, Andoni
A1  - Sancho, Ana
A1  - Götz, Ralph
A1  - Eiring, Patrick
A1  - Walz, Susanne
A1  - Jetani, Hardikkumar
A1  - Gil-Pulido, Jesus
A1  - Da Via, Matteo Claudio
A1  - Teufel, Eva
A1  - Rhodes, Nadine
A1  - Haertle, Larissa
A1  - Arellano-Viera, Estibaliz
A1  - Tibes, Raoul
A1  - Rosenwald, Andreas
A1  - Rasche, Leo
A1  - Hudecek, Michael
A1  - Sauer, Markus
A1  - Groll, Jürgen
A1  - Einsele, Hermann
A1  - Kraus, Sabrina
A1  - Kortüm, Martin K.
T1  - Actin cytoskeleton deregulation confers midostaurin resistance in FLT3-mutant acute myeloid leukemia
JF  - Communications Biology
N2  - The presence of FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) is one of the most frequent mutations in acute myeloid leukemia (AML) and is associated with an unfavorable prognosis. FLT3 inhibitors, such as midostaurin, are used clinically but fail to entirely eradicate FLT3-ITD+AML. This study introduces a new perspective and highlights the impact of RAC1-dependent actin cytoskeleton remodeling on resistance to midostaurin in AML. RAC1 hyperactivation leads resistance via hyperphosphorylation of the positive regulator of actin polymerization N-WASP and antiapoptotic BCL-2. RAC1/N-WASP, through ARP2/3 complex activation, increases the number of actin filaments, cell stiffness and adhesion forces to mesenchymal stromal cells (MSCs) being identified as a biomarker of resistance. Midostaurin resistance can be overcome by a combination of midostaruin, the BCL-2 inhibitor venetoclax and the RAC1 inhibitor Eht1864 in midostaurin-resistant AML cell lines and primary samples, providing the first evidence of a potential new treatment approach to eradicate FLT3-ITD+AML. Garitano-Trojaola et al. used a combination of human acute myeloid leukemia (AML) cell lines and primary samples to show that RAC1-dependent actin cytoskeleton remodeling through BCL2 family plays a key role in resistance to the FLT3 inhibitor, Midostaurin in AML. They showed that by targeting RAC1 and BCL2, Midostaurin resistance was diminished, which potentially paves the way for an innovate treatment approach for FLT3 mutant AML.
KW  - actin
KW  - acute myeloid leukaemia
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-260709
VL  - 4
IS  - 1
ER  -