Pharmacologic targeting of the p62 ZZ domain enhances both anti-tumor and bone-anabolic effects of bortezomib in multiple myeloma

Haematologica. 2024 May 1;109(5):1501-1513. doi: 10.3324/haematol.2023.283787.

Abstract

Multiple myeloma (MM) is a malignancy of plasma cells whose antibody secretion creates proteotoxic stress relieved by the N-end rule pathway, a proteolytic system that degrades N-arginylated proteins in the proteasome. When the proteasome is inhibited, protein cargo is alternatively targeted for autophagic degradation by binding to the ZZ-domain of p62/ sequestosome-1. Here, we demonstrate that XRK3F2, a selective ligand for the ZZ-domain, dramatically improved two major responses to the proteasome inhibitor bortezomib (Btz) by increasing: i) killing of human MM cells by stimulating both Btz-mediated apoptosis and necroptosis, a process regulated by p62; and ii) preservation of bone mass by stimulating osteoblast differentiation and inhibiting osteoclastic bone destruction. Co-administration of Btz and XRK3F2 inhibited both branches of the bimodal N-end rule pathway exhibited synergistic anti-MM effects on MM cell lines and CD138+ cells from MM patients, and prevented stromal-mediated MM cell survival. In mice with established human MM, co-administration of Btz and XRK3F2 decreased tumor burden and prevented the progression of MM-induced osteolytic disease by inducing new bone formation more effectively than either single agent alone. The results suggest that p62-ZZ ligands enhance the anti- MM efficacy of proteasome inhibitors and can reduce MM morbidity and mortality by improving bone health.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects
  • Bortezomib* / pharmacology
  • Bortezomib* / therapeutic use
  • Cell Line, Tumor
  • Disease Models, Animal
  • Humans
  • Mice
  • Multiple Myeloma* / drug therapy
  • Multiple Myeloma* / metabolism
  • Multiple Myeloma* / pathology
  • Proteasome Inhibitors / pharmacology
  • Proteasome Inhibitors / therapeutic use
  • Protein Domains
  • Sequestosome-1 Protein / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Bortezomib
  • Sequestosome-1 Protein
  • Antineoplastic Agents
  • Proteasome Inhibitors