Journal Article

The Sec61 translocon is a therapeutic vulnerability in multiple myeloma

Mayau, Véronique, Dadaglio, Gilles, Demangel, Caroline, Domenger, Antoine, Deriano, Ludovic, Choisy, Caroline, Perthame, Emeline, Bories, Jean‐Christophe, Baron, Ludivine, Arnulf, Bertrand

2022

Overview

Multiple myeloma (MM) is an incurable malignancy characterized by the uncontrolled expansion of plasma cells in the bone marrow. While proteasome inhibitors like bortezomib efficiently halt MM progression, drug resistance inevitably develop, 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. In human MM cell lines, mycolactone caused rapid defects in secretion of immunoglobulins and expression of pro‐survival interleukin (IL)‐6 receptor and CD40, whose activation stimulates IL‐6 production. Mycolactone also triggered pro‐apoptotic endoplasmic reticulum stress responses synergizing with bortezomib for induction of MM cell death and overriding acquired resistance to the proteasome inhibitor. Notably, the mycolactone–bortezomib combination rapidly killed patient‐derived MM cells ex vivo , but not normal mononuclear cells. In immunodeficient mice engrafted with MM cells, it demonstrated superior therapeutic efficacy over single drug treatments, without inducing toxic side effects. Collectively, these findings establish Sec61 blockers as novel anti‐MM agents and reveal the interest of targeting both the translocon and the proteasome in proteostasis‐addicted tumors. Synopsis In this work, a pathogen‐derived inhibitor named mycolactone was used to demonstrate that the Sec61 translocon is a therapeutic target in Multiple Myeloma (MM). Inhibiting Sec61 in MM cells triggers unresolvable ER stress. Sec61 blockade synergizes with proteasome inhibition in MM for induction of terminal UPR. Mycolactone toxicity and synergy with bortezomib are conserved in MM cells with acquired resistance to proteasome inhibitors. Combining mycolactone with bortezomib delays MM xenograft growth in mice. Tumor cells from both naïve and relapsed MM patients are highly susceptible to Sec61 blockade. Graphical Abstract In this work, a pathogen‐derived inhibitor named mycolactone was used to demonstrate that the Sec61 translocon is a therapeutic target in Multiple Myeloma (MM).

• Publisher: Nature Publishing Group UK,EMBO Press,Wiley Open Access,John Wiley and Sons Inc,Springer Nature
• Subject: Animals / Antineoplastic Agents - pharmacology / Antineoplastic Agents - therapeutic use / Apoptosis / Biology / Bone marrow / Bortezomib / CD40 antigen / Cell death / Cell division / Cell Line, Tumor / Cellular stress response / Chemotherapy / Drug dosages / Drug resistance / EMBO03 / EMBO18 / Endoplasmic reticulum / Endoplasmic Reticulum Stress / Experiments / Humans / Immunodeficiency / Immunoglobulins / Immunology / Inhibitor drugs / Leukocytes (mononuclear) / Life Sciences / Malignancy / Mice / Multiple myeloma / Multiple Myeloma - drug therapy / Pathogens / Plasma cells / Proteasome Endopeptidase Complex - metabolism / Proteasome Inhibitors / Protein Transport / Proteins / proteostatic stress / SEC Translocation Channels - metabolism / Sec61 translocon / Tumors