A metabolic switch in proteasome inhibitor-resistant multiple myeloma ensures higher mitochondrial metabolism, protein folding and sphingomyelin synthesis

Besse, Lenka; Besse, Andrej; Mendez-Lopez, Max; Vašíčková, Kateřina; Sedláčková, Miroslava; Vaňhara, Petr; Kraus, Marianne; Bader, Jürgen; Ferreira, Renan B.; Castellano, Ronald K.; Law, Brian K.; Driessen, Christoph

doi:10.3324/haematol.2018.207704

Cited by 50 publications

(53 citation statements)

References 17 publications

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“…6i). Recently, it has been proposed that PI resistance can be overcome by targeting mitochondrial biology 45,46 . Interestingly, venetoclax, which targets mitochondria to induce apoptosis, also strongly synergized with E7107, potentially indicating some cross-talk between these mechanisms of anti-MM action (Fig.…”

Section: Srsf1 Phosphomimetic Has Weakened Spliceosome Interactionmentioning

confidence: 99%

Proteasome inhibitor-induced modulation reveals the spliceosome as a specific therapeutic vulnerability in multiple myeloma

et al. 2020

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Enhancing the efficacy of proteasome inhibitors (PI) is a central goal in myeloma therapy. We proposed that signaling-level responses after PI may reveal new mechanisms of action that can be therapeutically exploited. Unbiased phosphoproteomics after treatment with the PI carfilzomib surprisingly demonstrates the most prominent phosphorylation changes on splicing related proteins. Spliceosome modulation is invisible to RNA or protein abundance alone. Transcriptome analysis after PI demonstrates broad-scale intron retention, suggestive of spliceosome interference, as well as specific alternative splicing of protein homeostasis machinery components. These findings lead us to evaluate direct spliceosome inhibition in myeloma, which synergizes with carfilzomib and shows potent anti-tumor activity. Functional genomics and exome sequencing further support the spliceosome as a specific vulnerability in myeloma. Our results propose splicing interference as an unrecognized modality of PI mechanism, reveal additional modes of spliceosome modulation, and suggest spliceosome targeting as a promising therapeutic strategy in myeloma.

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Section: Srsf1 Phosphomimetic Has Weakened Spliceosome Interactionmentioning

confidence: 99%

Proteasome inhibitor-induced modulation reveals the spliceosome as a specific therapeutic vulnerability in multiple myeloma

et al. 2020

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“…The first rate-limiting step of glucose metabolism is its transport across the plasma membrane through glucose transporters (GLUT family) [ 113 ]. It was shown that MM cell lines expressing high levels of GLUT1, and consequently increased glucose uptake, respond synergistically to the combinatorial treatment of bortezomib with the GLUT1 inhibitor STF-31 [ 112 ].…”

Section: Emerging Proteasome Inhibitors Drug Combinations Targetinmentioning

confidence: 99%

“…A metabolomics profiling study showed that PI-resistant cells display massive alterations in cellular metabolism resulting in higher antioxidant capacity, higher redox homeostasis, and increased NAD+ levels [ 113 ]. This was a confirmation of previous studies where the NAD+ depleting agent FK866 was used with PIs to induce synergistic anti-MM cell death [ 42 , 117 ].…”

Section: Emerging Proteasome Inhibitors Drug Combinations Targetinmentioning

confidence: 99%

The Landscape of Signaling Pathways and Proteasome Inhibitors Combinations in Multiple Myeloma

Paradžik

Bandini

Mereu

et al. 2021

Cancers

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Multiple myeloma is a malignancy of terminally differentiated plasma cells, characterized by an extreme genetic heterogeneity that poses great challenges for its successful treatment. Due to antibody overproduction, MM cells depend on the precise regulation of the protein degradation systems. Despite the success of PIs in MM treatment, resistance and adverse toxic effects such as peripheral neuropathy and cardiotoxicity could arise. To this end, the use of rational combinatorial treatments might allow lowering the dose of inhibitors and therefore, minimize their side-effects. Even though the suppression of different cellular pathways in combination with proteasome inhibitors have shown remarkable anti-myeloma activities in preclinical models, many of these promising combinations often failed in clinical trials. Substantial progress has been made by the simultaneous targeting of proteasome and different aspects of MM-associated immune dysfunctions. Moreover, targeting deranged metabolic hubs could represent a new avenue to identify effective therapeutic combinations with PIs. Finally, epigenetic drugs targeting either DNA methylation, histone modifiers/readers, or chromatin remodelers are showing pleiotropic anti-myeloma effects alone and in combination with PIs. We envisage that the positive outcome of patients will probably depend on the availability of more effective drug combinations and treatment of early MM stages. Therefore, the identification of sensitive targets and aberrant signaling pathways is instrumental for the development of new personalized therapies for MM patients.

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“…For drug treatment experiments, cells were plated into 96 well plates and treated for 48 hours with compounds unless otherwise noted. For quantitative flow cytometry, antibodies used were FITC Mouse antihuman CD48 (BD Biosciences, clone TU145), FITC Mouse anti-human CD38 (BD Biosciences, clone HIT2), FITC Mouse IgG1k isotype control (BD Biosciences, clone [27][28][29][30][31][32][33][34][35], and unstained respectively. using calibrated beads (Bangs Labortories), 200 µL of FACS buffer + 1 drop of beads per well (one wells for "blank" beads, and other for FITC-Beads).…”

Section: Myeloma Patient Sample Processingmentioning

confidence: 99%

Defining the cell surface proteomic landscape of multiple myeloma reveals immunotherapeutic strategies and biomarkers of drug resistance

Ferguson

Escobar

Tuomivaara

et al. 2021

Preprint

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The myeloma cell surface proteome (“surfaceome”) not only determines tumor interaction with the microenvironment but serves as an emerging arena for therapeutic development. Here, we use glycoprotein capture proteomics to first define surface markers most-enriched on myeloma when compared to B-cell malignancy models, revealing unexpected biological signatures unique to malignant plasma cells. We next integrate our proteomic dataset with existing transcriptome databases, nominating CCR10 and TXNDC11 as possible monotherapeutic targets and CD48 as a promising co-target for increasing avidity of BCMA-directed cellular therapies. We further identify potential biomarkers of resistance to both proteasome inhibitors and lenalidomide including changes in CD53, EVI2B, CD10, and CD33. Comparison of short-term treatment with chronic resistance delineates large differences in surface proteome profile under each type of drug exposure. Finally, we develop a miniaturized version of the surface proteomics protocol and present the first surface proteomic profile of a primary myeloma patient plasma cell sample. Our dataset provides a unique resource to advance the biological, therapeutic, and diagnostic understanding of myeloma.

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A metabolic switch in proteasome inhibitor-resistant multiple myeloma ensures higher mitochondrial metabolism, protein folding and sphingomyelin synthesis

Cited by 50 publications

References 17 publications

Proteasome inhibitor-induced modulation reveals the spliceosome as a specific therapeutic vulnerability in multiple myeloma

Proteasome inhibitor-induced modulation reveals the spliceosome as a specific therapeutic vulnerability in multiple myeloma

The Landscape of Signaling Pathways and Proteasome Inhibitors Combinations in Multiple Myeloma

Defining the cell surface proteomic landscape of multiple myeloma reveals immunotherapeutic strategies and biomarkers of drug resistance

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