The fatty acid elongase ELOVL6 regulates bortezomib resistance in multiple myeloma

Lipchick, Brittany C.; Utley, Adam; Han, Zhannan; Moparthy, Sudha; Yun, Dong Hyun; Bianchi‐Smiraglia, Anna; Wolff, Dennis W.; Fink, Emily E.; Liu, Liang; Furdui, Cristina M.; Lee, Jingyun; Lee, Kelvin P.; Nikiforov, Mikhail A.

doi:10.1182/bloodadvances.2020002578

Cited by 15 publications

(8 citation statements)

References 73 publications

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“…Thus, our study represents a novel approach to reducing MYC by targeting the FABP family. This work also builds upon data that myeloma cells exhibit aberrant amino acid, lipid, and energy metabolism [44], and data revealing the importance of metabolic enzymes in myeloma tumorigenesis [45] and drug resistance [46] by demonstrating the role of FABPs in MM cell metabolism and mitochondrial integrity. In sum, we identified a new protein family for therapeutic targeting in myeloma, and demonstrated, for the first time, the great potential for inhibiting it in MM.…”

Section: Discussionmentioning

confidence: 94%

The Fatty Acid Binding Protein Family Represents a Novel Target in Multiple Myeloma

Farrell

Fairfield

Karam

et al. 2022

Preprint

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Background: Multiple myeloma is an incurable plasma cell malignancy with only a 53% 5-year survival rate, highlighting a critical need for new multiple myeloma vulnerabilities and therapeutic avenues. Herein, we explored a novel multiple myeloma target: the fatty acid binding protein (FABP) family. Methods: Myeloma cells treated with FABP inhibitors (BMS3094013 and SBFI-26) were examined in vivo and in vitro for cell cycle, proliferation, apoptosis, mitochondrial membrane potential, cellular metabolism (oxygen consumption rates and fatty acid oxidation), and DNA methylation. Myeloma cell responses to BMS309403 and/or SBFI-26 were assessed with RNA-sequencing and proteomic analysis, and confirmed with western blotting and qRT-PCR. Myeloma cell dependency on FABPs was assessed using DepMap. Finally, MM patient datasets (CoMMpass and GEO) were mined for FABP expression correlations with clinical outcomes. Results: Myeloma cells treated with FABPi or with FABP5 knockout (generated via CRISPR/Cas9 editing) exhibited diminished proliferation in vitro. FABPi had potent anti-tumor effects both in vitro and in vivo in two pre-clinical MM mouse models where increased mouse survival was observed. FABPi negatively impacted mitochondrial respiration and reduced expression of MYC and other key signaling pathways in MM cells. Clinical data demonstrated worse overall and progression-free survival in patients with high FABP5. Conclusions: This study establishes the FABP family as a therapeutically actionable dependency in multiple myeloma with a multitude of actions and cellular roles that result in the support of myeloma progression.

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Section: Discussionmentioning

confidence: 94%

The Fatty Acid Binding Protein Family Represents a Novel Target in Multiple Myeloma

Farrell

Fairfield

Karam

et al. 2022

Preprint

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“…As the use of an ACSS2 inhibitor reduced myeloma growth both in vitro and in a diet-induced obese mouse model, the critical role of ACSS2 in MM was verified (59). Another fatty acid metabolism gene, fatty acid elongase 6 (ELOVL6), was recently shown to regulate PI resistance in MM (80). We have found that the ACSL and FABP (fatty acid binding proteins) families of are other, novel potential targets in MM (81)(82)(83).…”

Section: Lipid Mediators and Metabolism-related Enzymesmentioning

confidence: 88%

Obesity and myeloma: Clinical and mechanistic contributions to disease progression

et al. 2023

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Obesity and obesogenic behaviors are positively associated with both monoclonal gammopathy of unknown significance (MGUS) and multiple myeloma (MM). As the only known modifiable risk factor, this association has emerged as a new potential target for MM prevention, but little is known about the mechanistic relationship of body weight with MM progression. Here we summarize epidemiological correlations between weight, body composition, and the various stages of myeloma disease progression and treatments, as well as the current understanding of the molecular contributions of obesity-induced changes in myeloma cell phenotype and signaling. Finally, we outline groundwork for the future characterization of the relationship between body weight patterns, the bone marrow microenvironment, and MM pathogenesis in animal models, which have the potential to impact our understanding of disease pathogenesis and inform MM prevention messages.

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“…BZ exerts its anti-tumor effect through ER stress caused by the protein accumulation ( 53 ), because the ER is the site of lipid synthesis, and BZ also causes lipid accumulation ( 45 ). In BZ-resistant MM, it was found that the expression of SREBP1 and its downstream target FA elongase ELOVL6 are reduced, resulting in inhibiting lipid synthesis, thereby reducing the accumulation on the ER and ultimately causing BZ-resistance ( 54 ). In addition to CD36 mediating cellular uptake of FAs, FATP also mediates cellular uptake of FAs.…”

Section: Fa Metabolism In Hematological Malignanciesmentioning

confidence: 99%

Reprogramming lipid metabolism as potential strategy for hematological malignancy therapy

Zhang

Chang²,

Liu³

et al. 2022

Front. Oncol.

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Hematological malignancies are one of the most lethal illnesses that seriously threaten human life and health. Lipids are important constituents of various biological membranes and substances for energy storage and cell signaling. Furthermore, lipids are critical in the normal physiological activities of cells. In the process of the lethal transformation of hematological malignancies, lipid metabolism reprogramming meets the material and energy requirements of rapidly proliferating and dividing tumor cells. A large number of studies have shown that dysregulated lipid metabolism, commonly occurs in hematological malignancies, mediating the proliferation, growth, migration, invasion, apoptosis, drug resistance and immune escape of tumor cells. Targeting the lipid metabolism pathway of hematological malignancies has become an effective therapeutic approach. This article reviews the oncogenic mechanisms of lipid metabolism reprogramming in hematological malignancies, including fatty acid, cholesterol and phospholipid metabolism, thereby offering an insight into targeting lipid metabolism in the treatment of hematological malignancies.

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The fatty acid elongase ELOVL6 regulates bortezomib resistance in multiple myeloma

Cited by 15 publications

References 73 publications

The Fatty Acid Binding Protein Family Represents a Novel Target in Multiple Myeloma

The Fatty Acid Binding Protein Family Represents a Novel Target in Multiple Myeloma

Obesity and myeloma: Clinical and mechanistic contributions to disease progression

Reprogramming lipid metabolism as potential strategy for hematological malignancy therapy

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