Targeting endoplasmic reticulum export disrupts metabolic resilience in multiple myeloma

Area of Science:

• Oncology
• Cell Biology
• Molecular Medicine

Background:

• Multiple myeloma (MM) cells heavily rely on proteostasis due to high immunoglobulin production.
• Current MM therapies often target protein degradation, neglecting protein biosynthesis pathways.
• The role of the biosynthetic branch of proteostasis in MM remains underexplored.

Purpose of the Study:

• To investigate the therapeutic potential of targeting COPII-dependent endoplasmic reticulum (ER) export in multiple myeloma.
• To elucidate the mechanisms by which ER export inhibition induces cell death in MM cells.

Main Methods:

• Inhibition of COPII-dependent ER export in MM cell lines and primary patient cells.
• Assessment of protein misfolding, ER-associated degradation (ERAD), and amino acid levels.
• Analysis of mTORC1 signaling and mitochondrial function.
• Evaluation of therapeutic efficacy in in vivo myeloma models.

Main Results:

• Inhibition of ER export induced cell death in a secretory status-dependent manner.
• Blocking ER export led to protein misfolding, ERAD activation, and increased cytosolic amino acids.
• mTORC1 signaling was activated, coupled with mitochondrial dysfunction, creating an energetic imbalance.
• Therapeutic efficacy was confirmed in preclinical in vivo models.

Conclusions:

• Targeting the ER export machinery represents a novel therapeutic strategy for multiple myeloma.
• The observed cell death is driven by an energetic crisis resulting from impaired ER export and mitochondrial dysfunction.
• This study highlights the ER export pathway as a vulnerable target in MM.