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

Area of Science:

• Oncology
• Molecular Biology
• Metabolic Pathways

Background:

• Multiple myeloma (MM) is a plasma cell malignancy.
• The t(4;14) translocation is associated with a poorer prognosis in MM patients.
• Understanding the unique dependencies of MM subtypes is crucial for targeted therapies.

Purpose of the Study:

• To investigate the metabolic vulnerabilities of t(4;14)-positive multiple myeloma cells.
• To explore the therapeutic potential of targeting the mevalonate pathway in this MM subtype.
• To evaluate the synergistic effects of statins and bortezomib in t(4;14)-positive MM.

Main Methods:

• Cell viability assays and apoptosis induction studies.
• Analysis of the integrated stress response (ISR) pathway.
• In vivo studies using mouse models of MM.

Main Results:

• t(4;14)-positive MM cells are critically dependent on the mevalonate (MVA) pathway.
• Statin treatment preferentially induced apoptosis in t(4;14)-positive cells by inhibiting the MVA pathway.
• Exogenous geranylgeranyl pyrophosphate (GGPP) rescued statin-induced apoptosis, highlighting its role in protein geranylgeranylation.
• Statin and bortezomib combination therapy synergistically increased apoptosis and anti-tumor activity in vivo.

Conclusions:

• The t(4;14) translocation identifies a metabolic vulnerability to statins in multiple myeloma.
• Targeting the MVA pathway, specifically protein geranylgeranylation, is a promising therapeutic strategy for t(4;14)-positive MM.
• Combination therapy with statins and bortezomib warrants further clinical investigation for t(4;14)-positive MM patients.