Proteasome inhibitors, the therapeutic backbone of current treatments for multiple myeloma, are effective in treating newly diagnosed disease, but resistance or intolerance to these molecules often develops, leading to relapse. While studying a neglected tropical disease, Buruli ulcer, researchers discovered a novel therapeutic target for multiple myeloma that could allow the bypassing of this resistance. The results of this study were published by Domenger et al in EMBO Molecular Medicine.
Sec61
Buruli ulcer is caused by infection with a bacterium (Mycobacterium ulcerans) and can cause severe and irreversible skin necrosis. Lesions are due to bacterial production of a toxin called mycolactone in infected skin. In 2016, a research team discovered how mycolactone causes the clinical manifestations of Buruli ulcer: by targeting the translocon (Sec61).
The translocon is a channel anchored in the wall of a cell compartment called the endoplasmic reticulum that plays a crucial role in the synthesis of a subset of proteins: those that are destined to be secreted in the extracellular medium. The translocon controls the import of these proteins into the endoplasmic reticulum, and it is the main gateway to the secretory pathway. By blocking Sec61, mycolactone retains these proteins inside the cell and provokes their degradation by the proteasome, a stressful process that can evolve towards programmed cell death.
Using murine models and tumors from patient biopsies, researchers demonstrated that mycolactone is highly toxic to multiple myeloma cells, including those that have become resistant to proteasome inhibitors, at doses that are non-toxic to normal cells. In addition, they showed that mycolactone and proteasome inhibitors work in synergy, mutually potentiating their anticancer effects.
“This study provides the proof of concept that the translocon is a new therapeutic target in multiple myeloma. The next step will be to identify drug-like molecules inhibiting Sec61, which could constitute a new treatment for this cancer. In addition, we aim to study whether this target could be common to other cancers,” explained senior study author Caroline Demangel, PhD, Head of the Immunobiology of Infection Unit at the Institut Pasteur.
The authors concluded, “These findings establish Sec61 blockers as novel anti–multiple myeloma agents and reveal the interest of targeting both the translocon and the proteasome in proteostasis-addicted tumors.”
Disclosure: For full disclosures of the study authors, visit embopress.org.
