Inhibition of Sec61 Translocon for Multiple Myeloma Treatment

Multiple myeloma (MM) is a type of blood cancer that is prompted by the malignancy of plasma cells, a type of white blood cell, that is progressively accumulated in the bone marrow. This disorder can bring about a number of medical issues that can affect not only a person’s body but also how it functions. One of the most prevalent side effects occurs in the form of bone pain, which increases the risk of bone fractures. This pain can come from mutated plasma cells that break down the interior of the bone’s tissue, resulting in osteolytic lesions, which are essentially soft spots in the bone. Other common side effects are damage to the organs (amyloidosis), kidney failure, the body’s inability to produce healthy red and white blood cells, and many other diseases. Those living with Multiple Myeloma overall have an estimated life expectancy of 5 years, and it is predicted that another 35,730 people in the United States will be diagnosed with this same condition. While there is still currently no known cure for multiple myeloma, the use of proteasome inhibitors (PI) has altered the management of MM, and since their introduction, they have become the backbone of MM therapeutic treatments. 

Proteasome inhibitors are a class of drugs that prevent the proteasome, a protein complex found in eukaryotic cells that plays an important role in protein quality control, by degrading obsolete proteins and converting them into new proteins, from performing protein recycling. Cancerous plasma cells are also capable of producing useless proteins in much greater quantities than normal cells. This is where proteasome inhibitors come in, when they inhibit the proteasome from disposing of all the unusable proteins, the ineffective proteins can build up until they blow up from this accumulated waste, and kill the cancerous cell. However, one of the major obstacles to PI treatment has been relapse, which occurs when MM and other malignancies begin to develop a resistance or intolerance to certain PI molecules. 

Scientists from the Institut Pasteur and Inserm recently identified a novel therapeutic target through research on the bacterium Mycobacterium ulcerans (Domenger 2022). This human pathogen is known to produce a toxin known as mycolactone, and it has been discovered that  inhibiting the translocon protein Sec61 acts as a therapeutic target for MM. 

The translocon is a protein channel located in the endoplasmic reticulum (ER) that facilitates the import of proteins into the ER for the synthesis of proteins. When targeting the pore of Sec61 in the translocon, mycolactone blocks the import of further proteins into the ER and retains proteins inside the cell, leading to the cell's death by the proteasome (Hall 2014). Researchers have demonstrated from tests utilizing murine models as well as tumors that inhibiting Sec61 with mycolactone is substantially more toxic to multiple myeloma cells that have even developed resistance to proteasome inhibitors than compared to normal cells (Domenger 2022). 

Based on this study and research that identifies Sec61 as a therapeutic vulnerability to multiple myeloma and other potential cancers that require an active Sec61 translocon for survival, the next step would be to find drug-like molecules that inhibit the Sec61 similarly to mycolactone which could constitute new treatments. This step is already underway in several science laboratories across the country.

Citations

Domenger, A., Choisy, C., & Baron, L. (2022). The SEC61 translocon is a therapeutic vulnerability in multiple myeloma. The Sec61 translocon is a therapeutic vulnerability in multiple myeloma. Retrieved from https://www.embopress.org/doi/full/10.15252/emmm.202114740  

Lang, S., Pfeffer, S., Lee, P.-H., Cavalié, A., Helms, V., Förster, F., & Zimmermann, R. (2017, October 19). An update on sec61 channel functions, mechanisms, and related diseases. Frontiers. Retrieved January 31, 2023, from https://www.frontiersin.org/articles/10.3389/fphys.2017.00887/full 

Manasanch, E. E., & Orlowski, R. Z. (2017, January 24). Proteasome inhibitors in cancer therapy. Nature News. Retrieved January 31, 2023, from https://www.nature.com/articles/nrclinonc.2016.206 

Key statistics for multiple myeloma. American Cancer Society. (2022). Retrieved from https://www.cancer.org/cancer/multiple-myeloma/about/key-statistics.html