The Sec61 translocon is a therapeutic vulnerability in multiple myeloma

Abstract

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.

Sec61 blockade therapy overrides resistance to proteasome inhibitors and immunomodulatory drugs in Multiple Myeloma

“…However, small Sec61 inhibitors with an enhanced therapeutic index were recently generated, some of which are currently evaluated in Oncology phase 1 trials [13]. Building on our previous study [7], the present work strengthens the notion that blocking Sec61 is a relevant approach for the treatment of refractory or relapsed MM.…”

“…Using mycolactone (Myco) as a model inhibitor, we recently reported that Sec61 (the channel mediating secretory protein import into the ER) is a therapeutic vulnerability in MM [7]. In MM cell lines and patientderived tumors, Myco triggered an atypical, pro-apoptotic ER stress response synergizing with Bz for induction of MM cell death in vitro and in vivo.…”

“…Other hallmarks of Bz activity include elevated splicing of X-box binding protein 1 (XBP1) mRNA into transcriptionally active sXBP1 and induction of the ER-resident chaperone BiP, a master regulator of the UPR controlling the threshold of apoptosis induction [9]. We previously reported that Myco synergizes with Bz by inducing an atypical UPR marked by hyper-activation of ATF4/CHOP signaling and XBP1 splicing, in the absence of BiP upregulation [7]. Figure 1E shows that the distinctive ER stress signatures of Bz, Myco and Bz+Myco were maintained in LenR MM1S cells (Figure 1E).…”

Multiple Myeloma Therapy: Emerging Trends and Challenges

“…Targeting the Sec61 of the translocon, thus disrupting transport of newly secreted or transmembrane proteins into the ER, leads to their degradation by the proteasome, which can eventually lead to cell apoptosis due to continuous proteotoxic stress response. The use of mycolactone, a small molecule that inhibits Sec61, along with PI was found to be effective in inducing apoptosis and synergistic in pre-clinical models of laboratory-derived MM cell lines [ 291 ]. This combination was found to cause enhanced ER stress with activation of pro-apoptotic UPR in MM cells, as reflected on transcript as well as protein levels.…”

“…The synergy was maintained in bortezomib-resistant MM.1S cell lines, as well as in patient-derived MM cells. This target should be further explored as a potential novel therapeutic approach and drug development [ 291 ].…”