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

Abstract Purpose Multiple Myeloma (MM) is an incurable neoplasm of mature B cells and the second most prevalent hematological malignancy worldwide. While combinations of proteasome inhibitors like bortezomib (Bz) and immunomodulators (IMIDs) like lenalinomide (Len) are generally effective in stopping MM development, treated patients will eventually become resistant to one or both of these drugs. Using MM cell lines and patient-derived tumors, we recently reported that blocking the Sec61 translocon with mycolactone triggers an atypical unfolded protein response synergizing with Bz to kill MM cells, and overriding resistance to Bz. To extend this work, here we examined how Sec61 blockade interferes with Len and whether it overcomes IMID resistance. Methods Using the MM1S model cell line and a previously established daughter with stable resistance to Bz, we genetically engineered two additional daughters with single and double resistance to Len and Bz. The four cell lines were then compared side by side for sensitivity to mycolactone, alone and combined to Bz and/or Len, in vitro and in vivo. Results The synergistic effect of mycolactone on Bz was maintained in both single and double drug resistant MM cells and notably, extended to Len. Double drug resistance even conferred MM cells with an increased sensitivity to Sec61 blockade. Notably, mycolactone enhanced the therapeutic efficacy of the Bz + Len combination in both mice engrafted with parental or double drug resistant MM1S. Conclusion These data support the interest of further evaluating Sec61 blockers in MM drug combinations and their potential for treatment of refractory or relapsed MM.