The Sec61 translocon is a therapeutic vulnerability in multiple myeloma

EMBO Mol Med. 2022 Mar 7;14(3):e14740. doi: 10.15252/emmm.202114740. Epub 2022 Jan 11.


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.

Keywords: Sec61 translocon; multiple myeloma; proteostatic stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents* / pharmacology
  • Antineoplastic Agents* / therapeutic use
  • Cell Line, Tumor
  • Endoplasmic Reticulum Stress
  • Humans
  • Mice
  • Multiple Myeloma* / drug therapy
  • Proteasome Endopeptidase Complex / metabolism
  • Proteasome Inhibitors
  • Protein Transport
  • SEC Translocation Channels / metabolism


  • Antineoplastic Agents
  • Proteasome Inhibitors
  • SEC Translocation Channels
  • Proteasome Endopeptidase Complex