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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.
Background: Scientific guidelines have been developed to update and harmonize exercise based cardiac rehabilitation (ebCR) in German speaking countries. Key recommendations for ebCR indications have recently been published in part 1 of this journal. The present part 2 updates the evidence with respect to contents and delivery of ebCR in clinical practice, focusing on exercise training (ET), psychological interventions (PI), patient education (PE). In addition, special patients' groups and new developments, such as telemedical (Tele) or home-based ebCR, are discussed as well. Methods: Generation of evidence and search of literature have been described in part 1. Results: Well documented evidence confirms the prognostic significance of ET in patients with coronary artery disease. Positive clinical effects of ET are described in patients with congestive heart failure, heart valve surgery or intervention, adults with congenital heart disease, and peripheral arterial disease. Specific recommendations for risk stratification and adequate exercise prescription for continuous-, interval-, and strength training are given in detail. PI when added to ebCR did not show significant positive effects in general. There was a positive trend towards reduction in depressive symptoms for “distress management” and “lifestyle changes”. PE is able to increase patients’ knowledge and motivation, as well as behavior changes, regarding physical activity, dietary habits, and smoking cessation. The evidence for distinct ebCR programs in special patients’ groups is less clear. Studies on Tele-CR predominantly included low-risk patients. Hence, it is questionable, whether clinical results derived from studies in conventional ebCR may be transferred to Tele-CR. Conclusions: ET is the cornerstone of ebCR. Additional PI should be included, adjusted to the needs of the individual patient. PE is able to promote patients self-management, empowerment, and motivation. Diversity-sensitive structures should be established to interact with the needs of special patient groups and gender issues. Tele-CR should be further investigated as a valuable tool to implement ebCR more widely and effectively.
Actin cytoskeleton deregulation confers midostaurin resistance in FLT3-mutant acute myeloid leukemia
(2021)
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.