ArticleLeukemia2021
The mevalonate pathway is an actionable vulnerability of t(4;14)-positive multiple myeloma.
Article in Leukemia, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 33 citations in OpenAlex.
- Statin exposure after multiple myeloma diagnosis and risk of all-cause mortality, venous thromboembolism, pathological fractures, and acute kidney injury: a propensity score-matched retrospective cohort study.Annals of medicine and surgery (2012) · 2026Article
- The integrated stress response in cancer: mechanisms of tumor adaptation and therapeutic targeting.Biochemical Society transactions · 2026Review
- Article
- Targeting Acetyl-CoA Carboxylase Suppresses De Novo Lipogenesis and Tumor Cell Growth in Multiple Myeloma.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Article
- NAD+ metabolism restriction boosts high-dose melphalan efficacy in patients with multiple myeloma.Blood advances · 2025Article
- Article
- Cholesterol metabolism reprogramming in multiple myeloma: examining its specificity and impact on the immune microenvironment.American journal of cancer research · 2025Review
- Modeling serum M-protein response for early detection of biochemical relapse in myeloma patients treated with bortezomib, lenalidomide and dexamethasone.CPT: pharmacometrics & systems pharmacology · 2024Article
- Class II ferroptosis inducers are a novel therapeutic approach for t(4;14)-positive multiple myeloma.Blood advances · 2024Article
- Discovering Potential in Non-Cancer Medications: A Promising Breakthrough for Multiple Myeloma Patients.Cancers · 2024Review
- Statin-induced Mitochondrial Priming Sensitizes Multiple Myeloma Cells to BCL2 and MCL-1 Inhibitors.Cancer research communications · 2023Article
- It is worth the weight: obesity and the transition from monoclonal gammopathy of undetermined significance to multiple myeloma.Blood advances · 2023Review
- Acetyl-CoA metabolism in cancer.Nature reviews. Cancer · 2023Review
- Artesunate induces ferroptosis by inhibiting the nuclear localization of SREBP2 in myeloma cells.International journal of medical sciences · 2023Article
- Geranylgeranyl diphosphate synthase: Role in human health, disease and potential therapeutic target.Clinical and translational medicine · 2023Review
- Targeting the Isoprenoid Biosynthetic Pathway in Multiple Myeloma.International journal of molecular sciences · 2022Review
- Computational pharmacogenomic screen identifies drugs that potentiate the anti-breast cancer activity of statins.Nature communications · 2022Article
- Metabolic Vulnerabilities in Multiple Myeloma.Cancers · 2022Review
- Abnormal lipid synthesis as a therapeutic target for cancer stem cells.World journal of stem cells · 2022Review
- Geranylgeranyl diphosphate synthase inhibitor and proteasome inhibitor combination therapy in multiple myeloma.Experimental hematology & oncology · 2022Article
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Authors and funding
12 authors at 5 institutions in 2 countries.
Funding
Abstract
Multiple myeloma (MM) is a plasma cell malignancy that is often driven by chromosomal translocations. In particular, patients with t(4;14)-positive disease have worse prognosis compared to other MM subtypes. Herein, we demonstrated that t(4;14)-positive cells are highly dependent on the mevalonate (MVA) pathway for survival. Moreover, we showed that this metabolic vulnerability is immediately actionable, as inhibiting the MVA pathway with a statin preferentially induced apoptosis in t(4;14)-positive cells. In response to statin treatment, t(4;14)-positive cells activated the integrated stress response (ISR), which was augmented by co-treatment with bortezomib, a proteasome inhibitor. We identified that t(4;14)-positive cells depend on the MVA pathway for the synthesis of geranylgeranyl pyrophosphate (GGPP), as exogenous GGPP fully rescued statin-induced ISR activation and apoptosis. Inhibiting protein geranylgeranylation similarly induced the ISR in t(4;14)-positive cells, suggesting that this subtype of MM depends on GGPP, at least in part, for protein geranylgeranylation. Notably, fluvastatin treatment synergized with bortezomib to induce apoptosis in t(4;14)-positive cells and potentiated the anti-tumor activity of bortezomib in vivo. Our data implicate the t(4;14) translocation as a biomarker of statin sensitivity and warrant further clinical evaluation of a statin in combination with bortezomib for the treatment of t(4;14)-positive disease.
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Registered trials
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