MYC dependency in GLS1 and NAMPT is a therapeutic vulnerability in multiple myeloma
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ABSTRACT:
PROVIDER: PRJNA1010798 | ENA |
REPOSITORIES: ENA
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Project description:Multiple myeloma is an incurable hematological malignancy evolving from precursor states to advanced phases of the disease. MYC abnormalities play a critical role in the disease progression. Nevertheless, MYC lacks therapeutic drugability, thereby necessitating the exploration of alternative strategies aimed at circumventing the challenges associated with targeting MYC. In this study, we hypothesized that MYC upregulation induces genomic dependencies in tumor cells, creating vulnerabilities that can be exploited therapeutically. We discovered a differential dependency on glutamine metabolism in MYC overexpressing cells. We functionally explored these dependencies as a selective targetable vulnerability in vitro and in vivo. Furthermore, we uncovered a potential synergistic combination that can exacerbated this metabolic vulnerability, Collectively, our in vitro and in vivo results revealed an effective therapeutic combinatory strategy in the context of MYC overexpressing MM.
2024-04-09 | PXD050010 | Pride
Project description:Multiple myeloma is an incurable hematological malignancy evolving from precursor states to advanced phases of the disease. MYC abnormalities play a critical role in the disease progression. Nevertheless, MYC lacks therapeutic drugability, thereby necessitating the exploration of alternative strategies aimed at circumventing the challenges associated with targeting MYC. In this study, we hypothesized that MYC upregulation induces genomic dependencies in tumor cells, creating vulnerabilities that can be exploited therapeutically. We discovered a differential dependency on glutamine metabolism in MYC overexpressing cells. We functionally explored these dependencies as a selective targetable vulnerability in vitro and in vivo. Furthermore, we uncovered a potential synergistic combinations that can exacerbated this metabolic vulnerability, Collectively, our in vitro and in vivo results revealed an effective therapeutic combinatory strategy in the context of MYC overexpressing MM.
2023-09-04 | GSE241948 | GEO
Project description:Multiple myeloma (MM) is an incurable hematological malignancy in which MYC alterations contribute to the malignant phenotype. Nevertheless, MYC lacks therapeutic druggability. Here, we leveraged large-scale loss-of-function screens and conducted a small molecule screen to identify genes and pathways with enhanced essentiality correlated with MYC expression. We reported a specific gene dependency in glutaminase (GLS1), essential for the viability and proliferation of MYC overexpressing cells. Conversely, the analysis of isogenic models, as well as cell lines dataset (CCLE) and patient datasets, revealed GLS1 as a non-oncogenic dependency in MYC-driven cells. We functionally delineated the differential modulation of glutamine to maintain mitochondrial function and cellular biosynthesis in MYC overexpressing cells. Furthermore, we observed that pharmaceutical inhibition of NAMPT selectively affects MYC upregulated cells. We demonstrate the effectiveness of combining GLS1 and NAMPT inhibitors, suggesting that targeting glutaminolysis and NAD synthesis may be a promising strategy to target MYC-driven MM.
| S-EPMC10952034 | biostudies-literature
Project description:Evaluation of specific coordinated pattern of transcriptional events consistent with anti-myeloma activity of FK866 (chemical Nampt inhibitor)
2012-11-05 | GSE35414 | GEO
Project description:Evaluation of specific coordinated pattern of transcriptional events consistent with anti-myeloma activity of FK866 (chemical Nampt inhibitor) 3 samples were analyzed using as control the untreated cells. Treated cells were cultured in presence of FK866 at concentration of 10nM for 6 and 24 hours.
2012-11-05 | E-GEOD-35414 | biostudies-arrayexpress
Project description:Resistance to proteasome inhibitors (PIs) is a ubiquitous clinical concern in multiple myeloma. We proposed that signaling-level responses after PI would reveal new means to enhance efficacy. Unbiased phosphoproteomics after the PI carfilzomib surprisingly demonstrated the most prominent phosphorylation changes on spliceosome components. Spliceosome modulation was invisible to RNA or protein abundance alone. Transcriptome analysis demonstrated broad-scale intron retention suggestive of PI-specific splicing interference. Direct spliceosome inhibition synergized with carfilzomib and showed potent anti-myeloma activity. Functional genomics and exome sequencing further supported 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.
2020-02-21 | PXD012172 | Pride
Project description:Protein Arginine Methyltransferase 1 is therapeutic vulnerability in Multiple Myeloma
| PRJNA983271 | ENA
Project description:Clinical progress in multiple myeloma (MM), an incurable plasma cell (PC) neoplasia, has been driven by therapies which have limited applications beyond MM/PC neoplasias and do not target specific oncogenic mutations in MM. Instead, these agents target pathways critical for PC biology yet largely dispensable for malignant or normal cells of most other lineages. We systematically characterized the lineage-preferential molecular dependencies of MM through genome-scale CRISPR gene editing studies in MM vs. hundreds of non-MM lines. This identified a collection of genes whose disruption has more pronounced or recurrent impact on the MM cell fitness compared to other malignancies. These genes, some known, others not previously linked to MM, encode transcription factors, chromatin modifiers, endoplasmic reticulum components, metabolic regulators or signaling molecules. The current dataset describes the transcriptional profiling of a MM cell line with CRISPR activation for the myeloma-preferential dependency, POU2AF1. The transcriptional profile of CRISPR activation of an additional gene (PANK1), which does not serve as a MM-preferential dependency in CRISPR gene editing studies, is also described.
2023-03-21 | GSE186997 | GEO
Project description:Patients with multiple myeloma refractory to standard treatments have short survival. High PDIA1 expression confers resistance to proteasome inhibitors and other stressors due to the gain in ER-function, while maintaining or increasing vulnerability to PDIA1 inhibition. In this study we report the identification and characterization of an orally bioavailable novel PDIA1 inhibitor CCF642-34 that is effective against multiple myeloma in pre-clinical models.
2021-02-20 | GSE167097 | GEO
Project description:Transcriptional profiling for CRISPR activation of a myeloma-preferential dependency
| PRJNA777245 | ENA