The mevalonate pathway is an actionable vulnerability of t(4;14)-positive multiple myeloma

Longo, Joseph; Смирнов, Петр; Li, Zhihua; Branchard, Emily; Leeuwen, Jenna E. van; Licht, Jonathan D.; Haibe‐Kains, Benjamin; Andrews, David W.; Pugh, Trevor J.; Trudel, Suzanne; Penn, Linda Z.

doi:10.1038/s41375-020-0962-2

Cited by 25 publications

(13 citation statements)

References 54 publications

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“…To date, there is one account in the literature that evaluates the benefit of combining IBP pathway inhibitors with PI therapy. This study shows that statins, which inhibit HMG-CoA reductase in the mevalonate pathway and lead to downstream disruption in isoprenoid synthesis, enhanced induction of apoptosis and UPR markers when used in combination with bortezomib in t (4;14)-positive MM cells [ 40 ]. Furthermore, using add-back studies they demonstrate that GGPP depletion drives apoptosis and UPR activation in their model.…”

Section: Discussionmentioning

confidence: 99%

Geranylgeranyl diphosphate synthase inhibitor and proteasome inhibitor combination therapy in multiple myeloma

et al. 2022

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Background Multiple myeloma (MM) remains an incurable malignancy, despite the advent of therapies such as proteosome inhibitors (PIs) that disrupt protein homeostasis and induce ER stress. We have pursued inhibition of geranylgeranyl diphosphate synthase (GGDPS) as a novel mechanism by which to target protein homeostasis in MM cells. GGDPS inhibitors (GGSI) disrupt Rab geranylgeranylation, which in turn results in perturbation of Rab-mediated protein trafficking, leading to accumulation of intracellular monoclonal protein, induction of ER stress and apoptosis. Our lead GGSI, RAM2061, has demonstrated favorable pharmacokinetic properties and in vivo efficacy. Here we sought to evaluate if combination therapy with GGSI and PI would result in enhanced disruption of the unfolded protein response (UPR) and increase anti-MM efficacy. Methods MTT assays were conducted to evaluate the cytotoxic effects of combining RAM2061 with bortezomib in human MM cells. The effects of RAM2061 and/or PI (bortezomib or carfilzomib) on markers of UPR and apoptosis were evaluated by a combination of immunoblot (ATF4, IRE1, p-eIF2a, cleaved caspases and PARP), RT-PCR (ATF4, ATF6, CHOP, PERK, IRE1) and flow cytometry (Annexin-V). Induction of immunogenic cell death (ICD) was assessed by immunoblot (HMGB1 release) and flow cytometry (calreticulin translocation). Cell assays were performed using both concurrent and sequential incubation with PIs. To evaluate the in vivo activity of GGSI/PI, a flank xenograft using MM.1S cells was performed. Results Isobologram analysis of cytotoxicity data revealed that sequential treatment of bortezomib with RAM2061 has a synergistic effect in MM cells, while concurrent treatment was primarily additive or mildly antagonistic. The effect of PIs on augmenting RAM2061-induced upregulation of UPR and apoptotic markers was dependent on timing of the PI exposure. Combination treatment with RAM2061 and bortezomib enhanced activation of ICD pathway markers. Lastly, combination treatment slowed MM tumor growth and lengthened survival in a MM xenograft model without evidence of off-target toxicity. Conclusion We demonstrate that GGSI/PI treatment can potentiate activation of the UPR and apoptotic pathway, as well as induce upregulation of markers associated with the ICD pathway. Collectively, these findings lay the groundwork for future clinical studies evaluating combination GGSI and PI therapy in patients with MM.

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Section: Discussionmentioning

confidence: 99%

Geranylgeranyl diphosphate synthase inhibitor and proteasome inhibitor combination therapy in multiple myeloma

et al. 2022

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“…Next to fatty acid synthesis, the mevalonate pathway was also implicated in t(4;14) MM. It was demonstrated that inhibition of the rate-limiting enzyme HMGCR by statin treatment is preferentially toxic to t(4;14) MM cells [ 221 ]. Inhibition of HMGCR through fluvastatin activated the integrated stress response (ISR), a stress response induced by ER stress and nutrient deprivation, amongst other things.…”

Section: Fgfr3 Deregulation In MMmentioning

confidence: 99%

Metabolic Effects of Recurrent Genetic Aberrations in Multiple Myeloma

Bloedjes

Wilde

Guikema

2021

Cancers

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Oncogene activation and malignant transformation exerts energetic, biosynthetic and redox demands on cancer cells due to increased proliferation, cell growth and tumor microenvironment adaptation. As such, altered metabolism is a hallmark of cancer, which is characterized by the reprogramming of multiple metabolic pathways. Multiple myeloma (MM) is a genetically heterogeneous disease that arises from terminally differentiated B cells. MM is characterized by reciprocal chromosomal translocations that often involve the immunoglobulin loci and a restricted set of partner loci, and complex chromosomal rearrangements that are associated with disease progression. Recurrent chromosomal aberrations in MM result in the aberrant expression of MYC, cyclin D1, FGFR3/MMSET and MAF/MAFB. In recent years, the intricate mechanisms that drive cancer cell metabolism and the many metabolic functions of the aforementioned MM-associated oncogenes have been investigated. Here, we discuss the metabolic consequences of recurrent chromosomal translocations in MM and provide a framework for the identification of metabolic changes that characterize MM cells.

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“…Many small GTPases, such as Ras and Rho, as members of the Ras superfamily of small GTPases involved in tumorigenesis, must be isoprenylated (25). Therefore, inhibiting the mevalonate pathway can reduce the isoprenylation of small GTPases, thereby inducing cancer cell death (26)(27)(28). In contrast, uncontrolled flux of mevalonate pathway metabolites promotes sustained Ras protein activation by constitutive prenylation, triggering malignant transformation (13).…”

Section: Discussionmentioning

confidence: 99%

Case Report: Mevalonic Aciduria Complicated by Acute Myeloid Leukemia After Hematopoietic Stem Cell Transplantation

Kim

Lee

et al. 2021

Front. Immunol.

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Mevalonic aciduria (MA) is the most severe clinical subtype of mevalonate kinase deficiency (MKD) caused by an inherited defect in the mevalonate pathway. The treatment of MKD focuses on the suppression of recurrent hyperinflammatory attacks using anti-inflammatory drugs. Recently, allogeneic hematopoietic stem cell transplantation (HCT) was shown to successfully ameliorate autoinflammatory attacks in patients with MKD. Here, we report a case of an infant who showed severe recurrent systemic inflammation and was diagnosed with MA. Although she responded to steroids, her symptoms relapsed after the dose was tapered, and organ deterioration occurred. Therefore, at the age of 11 months, HCT from a matched, unrelated donor was performed for curative treatment. However, at 50 days after transplantation, acute myeloid leukemia was diagnosed, which was chemo-refractory. A second HCT from her haploidentical father was performed to treat the acute myeloid leukemia, but the patient died of sepsis on day 4 after transplantation. This is the first report of malignancy following HCT for MA. Our findings suggest that normalizing the mevalonate pathway after HCT in patients with MKD impacts patients differently depending on the clinical spectrum and severity of disease.

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The mevalonate pathway is an actionable vulnerability of t(4;14)-positive multiple myeloma

Cited by 25 publications

References 54 publications

Geranylgeranyl diphosphate synthase inhibitor and proteasome inhibitor combination therapy in multiple myeloma

Geranylgeranyl diphosphate synthase inhibitor and proteasome inhibitor combination therapy in multiple myeloma

Metabolic Effects of Recurrent Genetic Aberrations in Multiple Myeloma

Case Report: Mevalonic Aciduria Complicated by Acute Myeloid Leukemia After Hematopoietic Stem Cell Transplantation

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