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

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.

• Authors: Joseph Longo, Petr Smirnov, Zhihua Li, Emily Branchard, Jenna E van Leeuwen, Jonathan D Licht, Benjamin Haibe-Kains, David W Andrews, Jonathan J Keats, Trevor J Pugh, Suzanne Trudel, Linda Z Penn
• Journal: Leukemia (Leukemia) Vol. 35 Issue 3 Pg. 796-808 (03 2021) ISSN: 1476-5551 [Electronic] England
• PMID: 32665698 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Biomarkers, Tumor
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Polyisoprenyl Phosphates
• Fluvastatin
• Bortezomib
• geranylgeranyl pyrophosphate
• Mevalonic Acid

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Biomarkers, Tumor (genetics, metabolism)
• Bortezomib (pharmacology)
• Cell Proliferation
• Chromosomes, Human, Pair 14
• Chromosomes, Human, Pair 4
• Female
• Fluvastatin (pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (pharmacology)
• Mevalonic Acid (metabolism)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Multiple Myeloma (drug therapy, genetics, metabolism, pathology)
• Polyisoprenyl Phosphates (pharmacology)
• Translocation, Genetic
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays