Multiple myeloma is a cancer that forms in a type of white blood cell called a plasma cell. In multiple myeloma, cancerous plasma cells accumulate in the bone marrow and crowd out healthy blood cells. Life expectancy is less than five years post-diagnosis. There are treatment options such as proteasome inhibitors that are effective in treating new cancers, however, resistance or intolerance to these molecules develop, leading to relapse. Now, researchers from the Institut Pasteur and Inserm, report they discovered a novel therapeutic target for multiple myeloma that could help overcome resistance.

Their findings are published in the journal EMBO Molecular Medicine in a paper titled, “The Sec61 translocon is a therapeutic vulnerability in multiple myeloma.”

“Multiple myeloma (MM) is an incurable malignancy characterized by the uncontrolled expansion of plasma cells in the bone marrow,” the researchers wrote. “While proteasome inhibitors like bortezomib efficiently halt MM progression, drug resistance inevitably develops, and novel therapeutic approaches are needed. Here, we used a recently discovered Sec61 inhibitor, mycolactone, to assess the interest of disrupting MM proteostasis via protein translocation blockade.”

The researchers in the Immunobiology of Infection Unit at the Institut Pasteur were studying the disease Buruli ulcer when they made the discovery.  In 2016, this team discovered how mycolactone causes the clinical manifestations of Buruli ulcer: by targeting the translocon (Sec61).

Using mice models and tumors from patient biopsies, researchers showed that mycolactone is toxic to multiple myeloma cells, including those that have become resistant to proteasome inhibitors. They also demonstrated 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 Caroline Demangel, head of the Immunobiology of Infection Unit at the Institut Pasteur.

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