Marino, SilviaPetrusca, Daniela N.Bishop, Ryan T.Anderson, Judith L.Sabol, Hayley M.Ashby, CodyLayer, Justin H.Cesarano, AnnamariaDavé, Utpal P.Perna, FabianaDelgado-Calle, JesusChirgwin, John M.Roodman, G. David2024-08-052024-08-052024-05-01Marino S, Petrusca DN, Bishop RT, et al. Pharmacologic targeting of the p62 ZZ domain enhances both anti-tumor and bone-anabolic effects of bortezomib in multiple myeloma. Haematologica. 2024;109(5):1501-1513. Published 2024 May 1. doi:10.3324/haematol.2023.283787https://hdl.handle.net/1805/42638Multiple 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.en-USAttribution-NonCommercial 4.0 InternationalAntineoplastic agentsBortezomibMultiple myelomaProteasome inhibitorsArticle