The proteasome is a central component of the protein degradation machinery in eukaryotic cells
Both transformed and normal cells depend on the function of the proteasome to control the expression of proteins linked to cell survival and proliferation
Clinical trials using proteasome inhibitors in myeloma, mantle-cell lymphoma (MCL) and amyloidosis have transformed the treatment of these diseases by establishing new standards of care
Three proteasome inhibitors have received regulatory approval and are used routinely in clinical settings, including bortezomib, carfilzomib and ixazomib
Primary resistance to proteasome inhibitors remains a challenge in patients with solid tumours; in addition, acquired resistance can be developed in myeloma and MCL even after initial responses, through mechanisms that are beginning to be understood
Clinical evaluation of compounds targeting the upstream regulatory components of the proteasome is underway; in the future, compounds that target proteasome-mediated degradation of specific proteins might also become available
The ubiquitin proteasome pathway was discovered in the 1980s to be a central component of the cellular protein-degradation machinery with essential functions in homeostasis, which include preventing the accumulation of misfolded or deleterious proteins. Cancer cells produce proteins that promote both cell survival and proliferation, and/or inhibit mechanisms of cell death. This notion set the stage for preclinical testing of proteasome inhibitors as a means to shift this fine equilibrium towards cell death. Since the late 1990s, clinical trials have been conducted for a variety of malignancies, leading to regulatory approvals of proteasome inhibitors to treat multiple myeloma and mantle-cell lymphoma. First-generation and second-generation proteasome inhibitors can elicit deep initial responses in patients with myeloma, for whom these drugs have dramatically improved outcomes, but relapses are frequent and acquired resistance to treatment eventually emerges. In addition, promising preclinical data obtained with proteasome inhibitors in models of solid tumours have not been confirmed in the clinic, indicating the importance of primary resistance. Investigation of the mechanisms of resistance is, therefore, essential to further maximize the utility of this class of drugs in the era of personalized medicine. Herein, we discuss the advances and challenges resulting from the introduction of proteasome inhibitors into the clinic.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Clusterin negatively modulates mechanical stress-mediated ligamentum flavum hypertrophy through TGF-β1 signaling
Experimental & Molecular Medicine Open Access 21 September 2022
Pan-cancer analysis of genomic and transcriptomic data reveals the prognostic relevance of human proteasome genes in different cancer types
BMC Cancer Open Access 19 September 2022
Journal of Biomedical Science Open Access 13 September 2022
Subscribe to Nature+
Get immediate online access to the entire Nature family of 50+ journals
Subscribe to Journal
Get full journal access for 1 year
only $8.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Orlowski, M. & Michaud, C. Pituitary multicatalytic proteinase complex. Specificity of components and aspects of proteolytic activity. Biochemistry 28, 9270–9278 (1989).
Glickman, M. H. & Ciechanover, A. The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol. Rev. 82, 373–428 (2002).
Schwartz, A. L. & Ciechanover, A. Targeting proteins for destruction by the ubiquitin system: implications for human pathobiology. Annu. Rev. Pharmacol. Toxicol. 49, 73–96 (2009).
Manasanch, E. E. et al. The proteasome: mechanisms of biology and markers of activity and response to treatment in multiple myeloma. Leuk. Lymphoma 55, 1707–1714 (2014).
Murata, S., Takahama, Y. & Tanaka, K. Thymoproteasome: probable role in generating positively selecting peptides. Curr. Opin. Immunol. 20, 192–196 (2008).
Garcia-Mata, R., Bebok, Z., Sorscher, E. J. & Sztul, E. S. Characterization and dynamics of aggresome formation by a cytosolic GFP-chimera. J. Cell Biol. 146, 1239–1254 (1999).
Orlowski, R. Z. & Dees, E. C. The role of the ubiquitination-proteasome pathway in breast cancer: applying drugs that affect the ubiquitin-proteasome pathway to the therapy of breast cancer. Breast Cancer Res. 5, 1–7 (2003).
Orlowski, R. Z. & Baldwin, A. S. Jr. NF-kappaB as a therapeutic target in cancer. Trends Mol. Med. 8, 385–389 (2002).
Lu, Z. & Hunter, T. Ubiquitylation and proteasomal degradation of the p21(Cip1), 27(Kip1) and p57(Kip2) CDK inhibitors. Cell Cycle 9, 2342–2352 (2010).
Love, I. M., Shi, D. & Grossman, S. R. p53 ubiquitination and proteasomal degradation. Methods Mol. Biol. 962, 63–73 (2013).
Orlowski, M. & Wilk, S. Catalytic activities of the 20 S proteasome, a multicatalytic proteinase complex. Arch. Biochem. Biophys. 383, 1–16 (2000).
Robak, T. et al. Bortezomib-based therapy for newly diagnosed mantle-cell lymphoma. N. Engl. J. Med. 372, 944–953 (2015).
Orlowski, R. Z. et al. Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J. Clin. Oncol. 20, 4420–4427 (2002).
Richardson, P. G. et al. Extended follow-up of a phase II trial in relapsed, refractory multiple myeloma:: final time-to-event results from the SUMMIT trial. Cancer 106, 1316–1319 (2006).
Richardson, P. G. et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N. Engl. J. Med. 348, 2609–2617 (2003).
Richardson, P. G. et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N. Engl. J. Med. 352, 2487–2498 (2005).
San Miguel, J. F. et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N. Engl. J. Med. 359, 906–917 (2008).
Richardson, P. G. et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood 116, 679–686 (2010).
Durie, B. G. M. et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet http://dx.doi.org/10.1016/S0140-6736(16)31594-X (2016).
Sonneveld, P. et al. Bortezomib-based versus nonbortezomib-based induction treatment before autologous stem-cell transplantation in patients with previously untreated multiple myeloma: a meta-analysis of phase III randomized, controlled trials. J. Clin. Oncol. 31, 3279–3287 (2013).
Sonneveld, P. et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J. Clin. Oncol. 30, 2946–2955 (2012).
Orlowski, R. Z. et al. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J. Clin. Oncol. 25, 3892–3901 (2007).
San-Miguel, J. F. et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. 15, 1195–1206 (2014).
Hideshima, T. et al. Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma. Proc. Natl Acad. Sci. USA 102, 8567–8572 (2005).
Shah, J. et al. Phase I/II trial of the efficacy and safety of combination therapy with lenalidomide/bortezomib/dexamethasone (RVD) and panobinostat in transplant-eligible patients with newly diagnosed multiple myeloma. Blood 126, 187 (2015).
Petrucci, M. T. et al. A prospective, international phase 2 study of bortezomib retreatment in patients with relapsed multiple myeloma. Br. J. Haematol. 160, 649–659 (2013).
Palumbo, A. et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N. Engl. J. Med. 375, 754–766 (2016).
Wang, Y. et al. Once- versus twice-weekly Bortezomib induction therapy with dexamethasone in newly diagnosed multiple myeloma. J. Huazhong Univ. Sci. Technolog. Med. Sci. 32, 495–500 (2012).
Moreau, P. et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 12, 431–440 (2011).
Arastu-Kapur, S. et al. Nonproteasomal targets of the proteasome inhibitors bortezomib and carfilzomib: a link to clinical adverse events. Clin. Cancer Res. 17, 2734–2743 (2011).
Lonial, S. et al. Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma. Blood 106, 3777–3784 (2005).
Chanan-Khan, A. et al. Analysis of herpes zoster events among bortezomib-treated patients in the phase III APEX study. J. Clin. Oncol. 26, 4784–4790 (2008).
O'Connor, O. A. et al. A phase 1 dose escalation study of the safety and pharmacokinetics of the novel proteasome inhibitor carfilzomib (PR-171) in patients with hematologic malignancies. Clin. Cancer Res. 15, 7085–7091 (2009).
Alsina, M. et al. A phase I single-agent study of twice-weekly consecutive-day dosing of the proteasome inhibitor carfilzomib in patients with relapsed or refractory multiple myeloma or lymphoma. Clin. Cancer Res. 18, 4830–4840 (2012).
Durie, B. G. et al. International uniform response criteria for multiple myeloma. Leukemia 20, 1467–1473 (2006).
Siegel, D. S. et al. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood 120, 2817–2825 (2012).
Ludwig, H. et al. Carfilzomib versus low-dose corticosteroids and optional cyclophosphamide in patients with relapsed and refractory multiple myeloma (RRMM): results from a phase 3 study (focus). Ann. Oncol. 25, v1–v41 (2014).
Hajek, R., Bryce, R., Ro, S., Klencke, B. & Ludwig, H. Design and rationale of FOCUS (PX-171-011): a randomized, open-label, phase 3 study of carfilzomib versus best supportive care regimen in patients with relapsed and refractory multiple myeloma (R/R MM). BMC Cancer 12, 415 (2012).
Stewart, A. K. et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N. Engl. J. Med. 372, 142–152 (2015).
Lendvai, N. et al. A phase 2 single-center study of carfilzomib 56 mg/m2 with or without dexamethasone in relapsed multiple myeloma. Blood 124, 899–906 (2014).
Dimopoulos, M. A. et al. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. Lancet Oncol. 17, 27–38 (2016).
Berenson, J. R. et al. Updated results from CHAMPION-1, a phase I/II study investigating weekly carfilzomib with dexamethasone for patients (Pts) with relapsed or refractory multiple myeloma (RRMM) [abstract]. J. Clin. Oncol. 33 (Suppl.), 8527 (2015).
Jakubowiak, A. J. et al. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood 120, 1801–1809 (2012).
Korde, N. et al. Treatment with carfilzomib-lenalidomide-dexamethasone with lenalidomide extension in patients with smoldering or newly diagnosed multiple myeloma. JAMA Oncol. 1, 746–754 (2015).
Benboubker. L. et al. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N. Engl. J. Med. 371, 906–917 (2014).
Dytfeld, D. et al. Carfilzomib, lenalidomide, and low-dose dexamethasone in elderly patients with newly diagnosed multiple myeloma. Haematologica 99, e162–e164 (2014).
Moreau, P. et al. Phase 1/2 study of carfilzomib plus melphalan and prednisone in patients aged over 65 years with newly diagnosed multiple myeloma. Blood 125, 3100–3104 (2015).
Chari, A. & Hajje, D. Case series discussion of cardiac and vascular events following carfilzomib treatment: possible mechanism, screening, and monitoring. BMC Cancer 14, 915 (2014).
Siegel, D. et al. Integrated safety profile of single-agent carfilzomib: experience from 526 patients enrolled in 4 phase II clinical studies. Haematologica 98, 1753–1761 (2013).
Kumar, S. K. et al. Phase 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma. Blood 124, 1047–1055 (2014).
Kumar, S. K. et al. Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label phase 1/2 study. Lancet Oncol. 15, 1503–1512 (2014).
Richardson, P. G. et al. Phase 1 study of twice-weekly ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma patients. Blood 124, 1038–1046 (2014).
Moreau, P. et al. Ixazomib, an investigational oral proteasome inhibitor (PI), in combination with lenalidomide and dexamethasone (IRd), significantly extends progression-free survival (PFS) for patients (Pts) with relapsed and/or refractory multiple myeloma (RRMM): the phase 3 Tourmaline-MM1 study [abstract]. Blood 126, 727 (2015).
Shah, J. et al. Oprozomib, pomalidomide, dexamethasone (OPomd) patients (Pts) with relapsed and/ refractory multiple myeloma (RRMM): initial results phase 1b Study. Blood 126, 378 (2015).
Vij, R. et al. Clinical profile of single-agent oprozomib in patients (Pts) with multiple myeloma (MM): updated results from a multicenter, open-label, dose escalation phase 1b/2 study [abstract]. Blood 124, 34 (2014).
Parameswaran, H. et al. Oprozomib and dexamethasone in patients with relapsed and/or refractory multiple myeloma: initial results from the dose escalation portion of a phase 1b/2, multicenter, open-label study [abstract]. Blood 124, 3453 (2014).
Potts, B. et al. Marizomib, a proteasome inhibitor for all seasons: preclinical profile and a framework for clinical trials. Curr. Cancer Drug Targets 11, 254–284 (2011).
Millward, M. et al. Phase 1 clinical trial of the novel proteasome inhibitor marizomib with the histone deacetylase inhibitor vorinostat in patients with melanoma, pancreatic and lung cancer based on in vitro assessments of the combination. Invest. New Drugs 30, 2303–2317 (2012).
Goy, A. et al. Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin's lymphoma. J. Clin. Oncol. 23, 667–675 (2005).
O'Connor, O. A. et al. Phase II clinical experience with the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkin's lymphoma and mantle cell lymphoma. J. Clin. Oncol. 23, 676–684 (2005).
Strauss, S. J. et al. Bortezomib therapy in patients with relapsed or refractory lymphoma: potential correlation of in vitro sensitivity and tumor necrosis factor alpha response with clinical activity. J. Clin. Oncol. 24, 2105–2112 (2006).
Fisher, R. I. et al. Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J. Clin. Oncol. 24, 4867–4874 (2006).
Belch, A. et al. A phase II study of bortezomib in mantle cell lymphoma: the National Cancer Institute of Canada Clinical Trials Group trial IND.150. Ann. Oncol. 18, 116–121 (2007).
Gerecitano, J. et al. Phase 2 study of weekly bortezomib in mantle cell and follicular lymphoma. Br. J. Haematol. 146, 652–655 (2009).
Till, B. G. et al. Phase II trial of R-CHOP plus bortezomib induction therapy followed by bortezomib maintenance for newly diagnosed mantle cell lymphoma: SWOG S0601. Br. J. Haematol. 172, 208–218 (2016).
Lenz, G. et al. Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). J. Clin. Oncol. 23, 1984–1992 (2005).
Dimopoulos, M. A. et al. Primary therapy of Waldenstrom macroglobulinemia (WM) with weekly bortezomib, low-dose dexamethasone, and rituximab (BDR): long-term results of a phase 2 study of the European Myeloma Network (EMN). Blood 122, 3276–3282 (2013).
Ghobrial, I. M. et al. Phase II trial of weekly bortezomib in combination with rituximab in untreated patients with Waldenstrom macroglobulinemia. Am. J. Hematol. 85, 670–674 (2010).
Treon, S. P. et al. Primary therapy of Waldenstrom macroglobulinemia with bortezomib, dexamethasone, and rituximab: WMCTG clinical trial 05–180. J. Clin. Oncol. 27, 3830–3835 (2009).
Treon, S. P. et al. Carfilzomib, rituximab, and dexamethasone (CaRD) treatment offers a neuropathy-sparing approach for treating Waldenstrom's macroglobulinemia. Blood 124, 503–510 (2014).
Sanchorawala, V. et al. Induction therapy with bortezomib followed by bortezomib-high dose melphalan and stem cell transplantation for AL amyloidosis: results of a prospective clinical trial. Biol. Blood Marrow Transplant. 21, 1445–1451 (2015).
Mikhael, J. R. et al. Cyclophosphamide-bortezomib-dexamethasone (CyBorD) produces rapid and complete hematologic response in patients with AL amyloidosis. Blood 119, 4391–4394 (2012).
Palladini, G. et al. A European collaborative study of cyclophosphamide, bortezomib, and dexamethasone in upfront treatment of systemic AL amyloidosis. Blood 126, 612–615 (2015).
Kastritis, E. et al. A randomized phase III trial of melphalan and dexamethasone (MDex) versus bortezomib, melphalan and dexamethasone (BMDex) for untreated patients with AL amyloidosis [abstract]. Blood 124, 35 (2014).
Attar, E. C. et al. Bortezomib added to daunorubicin and cytarabine during induction therapy and to intermediate-dose cytarabine for consolidation in patients with previously untreated acute myeloid leukemia age 60 to 75 years: CALGB (Alliance) study 10502. J. Clin. Oncol. 31, 923–929 (2013).
Attar, E. C. et al. Phase I dose escalation study of bortezomib in combination with lenalidomide in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Leuk. Res. 37, 1016–1020 (2013).
Blum, W. et al. Clinical and pharmacodynamic activity of bortezomib and decitabine in acute myeloid leukemia. Blood 119, 6025–6031 (2012).
Messinger, Y. H. et al. Bortezomib with chemotherapy is highly active in advanced B-precursor acute lymphoblastic leukemia: Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) Study. Blood 120, 285–290 (2012).
Huang, Z. et al. Efficacy of therapy with bortezomib in solid tumors: a review based on 32 clinical trials. Future Oncol. 10, 1795–1807 (2014).
Piperdi, B., Ling, Y. H., Liebes, L., Muggia, F. & Perez-Soler, R. Bortezomib: understanding the mechanism of action. Mol. Cancer Ther. 10, 2029–2030 (2011).
Woodle, E. S., Alloway, R. R. & Girnita, A. Proteasome inhibitor treatment of antibody-mediated allograft rejection. Curr. Opin. Organ Transplant. 16, 434–438 (2011).
Neubert, K. et al. The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis. Nat. Med. 14, 748–755 (2008).
Hiepe, F. et al. Long-lived autoreactive plasma cells drive persistent autoimmune inflammation. Nat. Rev. Rheumatol. 7, 170–178 (2011).
Gomez, A. M. et al. Proteasome inhibition with bortezomib depletes plasma cells and autoantibodies in experimental autoimmune myasthenia gravis. J. Immunol. 186, 2503–2513 (2011).
Bontscho, J. et al. Myeloperoxidase-specific plasma cell depletion by bortezomib protects from anti-neutrophil cytoplasmic autoantibodies-induced glomerulonephritis. J. Am. Soc. Nephrol. 22, 336–348 (2011).
Cenci, S. et al. Progressively impaired proteasomal capacity during terminal plasma cell differentiation. EMBO J. 25, 1104–1113 (2006).
Zinszner, H. et al. CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev. 12, 982–995 (1998).
Brewer, J. W. & Diehl, J. A. PERK mediates cell- cycle exit during the mammalian unfolded protein response. Proc. Natl Acad. Sci. USA 97, 12625–12630 (2000).
Annunziata, C. M. et al. Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma. Cancer Cell 12, 115–130 (2007).
Hideshima, T. et al. NF-kappa B as a therapeutic target in multiple myeloma. J. Biol. Chem. 277, 16639–16647 (2002).
Cenci, S. et al. Pivotal Advance: protein synthesis modulates responsiveness of differentiating and malignant plasma cells to proteasome inhibitors. J. Leukoc. Biol. 92, 921–931 (2012).
Bianchi, G. et al. The proteasome load versus capacity balance determines apoptotic sensitivity of multiple myeloma cells to proteasome inhibition. Blood 113, 3040–3049 (2009).
Meister, S. et al. Extensive immunoglobulin production sensitizes myeloma cells for proteasome inhibition. Cancer Res. 67, 1783–1792 (2007).
Melnick, J., Dul, J. L. & Argon, Y. Sequential interaction of the chaperones BiP and GRP94 with immunoglobulin chains in the endoplasmic reticulum. Nature 370, 373–375 (1994).
Obeng, E. A. et al. Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood 107, 4907–4916 (2006).
Lu, S. et al. Point mutation of the proteasome beta5 subunit gene is an important mechanism of bortezomib resistance in bortezomib-selected variants of Jurkat T cell lymphoblastic lymphoma/leukemia line. J. Pharmacol. Exp. Ther. 326, 423–431 (2008).
Lu, S. et al. Different mutants of PSMB5 confer varying bortezomib resistance in T lymphoblastic lymphoma/leukemia cells derived from the Jurkat cell line. Exp. Hematol. 37, 831–837 (2009).
Oerlemans, R. et al. Molecular basis of bortezomib resistance: proteasome subunit beta5 (PSMB5) gene mutation and overexpression of PSMB5 protein. Blood 112, 2489–2499 (2008).
Chapman, M. A. et al. Initial genome sequencing and analysis of multiple myeloma. Nature 471, 467–472 (2011).
Lichter, D. I. et al. Sequence analysis of beta-subunit genes of the 20S proteasome in patients with relapsed multiple myeloma treated with bortezomib or dexamethasone. Blood 120, 4513–4516 (2012).
Wang, L. et al. Proteasome beta subunit pharmacogenomics: gene resequencing and functional genomics. Clin. Cancer Res. 14, 3503–3513 (2008).
Fujiwara, T. et al. Proteasomes are essential for yeast proliferation. cDNA cloning and gene disruption of two major subunits. J. Biol. Chem. 265, 16604–16613 (1990).
Fuchs, D., Berges, C., Opelz, G., Daniel, V. & Naujokat, C. Increased expression and altered subunit composition of proteasomes induced by continuous proteasome inhibition establish apoptosis resistance and hyperproliferation of Burkitt lymphoma cells. J. Cell. Biochem. 103, 270–283 (2008).
Ruckrich, T. et al. Characterization of the ubiquitin-proteasome system in bortezomib-adapted cells. Leukemia 23, 1098–1105 (2009).
Kuhn, D. J. et al. Targeting the insulin-like growth factor-1 receptor to overcome bortezomib resistance in preclinical models of multiple myeloma. Blood 120, 3260–3270 (2012).
Mitsiades, N. et al. Molecular sequelae of proteasome inhibition in human multiple myeloma cells. Proc. Natl Acad. Sci. USA 99, 14374–14379 (2002).
Lianos, G. D. et al. The role of heat shock proteins in cancer. Cancer Lett. 360, 114–118 (2015).
Mitsiades, C. S. et al. Antimyeloma activity of heat shock protein-90 inhibition. Blood 107, 1092–1100 (2006).
Richardson, P. G. et al. PANORAMA 2: panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory myeloma. Blood 122, 2331–2337 (2013).
Lonial, S. et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet 387, 1551–1560 (2016).
Egan, J. B. et al. Whole-genome sequencing of multiple myeloma from diagnosis to plasma cell leukemia reveals genomic initiating events, evolution, and clonal tides. Blood 120, 1060–1066 (2012).
Hideshima, T. et al. Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells. Blood 107, 4053–4062 (2006).
Spencer, A. et al. The novel AKT inhibitor afuresertib shows favorable safety, pharmacokinetics, and clinical activity in multiple myeloma. Blood 124, 2190–2195 (2014).
Stessman, H. A. et al. Profiling bortezomib resistance identifies secondary therapies in a mouse myeloma model. Mol. Cancer Ther. 12, 1140–1150 (2013).
Weniger, M. A. et al. Treatment-induced oxidative stress and cellular antioxidant capacity determine response to bortezomib in mantle cell lymphoma. Clin. Cancer Res. 17, 5101–5112 (2011).
Li, B. et al. The nuclear factor (erythroid-derived 2)-like 2 and proteasome maturation protein axis mediates bortezomib resistance in multiple myeloma. J. Biol. Chem. 290, 29854–29868 (2015).
Leung-Hagesteijn, C. et al. Xbp1s-negative tumor B cells and pre-plasmablasts mediate therapeutic proteasome inhibitor resistance in multiple myeloma. Cancer Cell 24, 289–304 (2013).
Reimold, A. M. et al. Plasma cell differentiation requires the transcription factor XBP-1. Nature 412, 300–307 (2001).
Perez-Galan, P. et al. Bortezomib resistance in mantle cell lymphoma is associated with plasmacytic differentiation. Blood 117, 542–552 (2011).
Zhang, X.-D. et al. Tight junction protein 1 modulates proteasome capacity and proteasome inhibitor sensitivity in multiple myeloma through EGFR/JAK1/STAT3 signaling. Cancer Cell 29, 639–652 (2016).
Kimura, H., Caturegli, P., Takahashi, M. & Suzuki, K. New insights into the function of the immunoproteasome in immune and nonimmune cells. J. Immunol. Res. 2015, 541984 (2015).
Shah, J. J. et al. Phase I study of the novel investigational NEDD8-activating enzyme inhibitor pevonedistat (MLN4924) in patients with relapsed/refractory multiple myeloma or lymphoma. Clin. Cancer Res. 22, 34–43 (2016).
Swords, R. T. et al. Pevonedistat (MLN4924), a First-in-Class NEDD8-activating enzyme inhibitor, in patients with acute myeloid leukaemia and myelodysplastic syndromes: a phase 1 study. Br. J. Haematol. 169, 534–543 (2015).
Andreeff, M. et al. Results of the phase I trial of RG7112, a small-molecule MDM2 antagonist in leukemia. Clin. Cancer Res. 22, 868–876 (2016).
Sakamoto, K. M. et al. Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proc. Natl Acad. Sci. USA 98, 8554–8559 (2001).
Sakamoto, K. M. et al. Development of protacs to target cancer-promoting proteins for ubiquitination and degradation. Mol. Cell. Proteomics 2, 1350–1358 (2003).
Winter, G. E. et al. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science 348, 1376–1381 (2015).
Ito, T. et al. Identification of a primary target of thalidomide teratogenicity. Science 327, 1345–1350 (2010).
Zhu, Y. X. et al. Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide. Blood 118, 4771–4779 (2012).
Lu, G. et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science 343, 305–309 (2014).
Gandhi, A. K. et al. Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4 (CRBN.). Br. J. Haematol. 164, 811–821 (2014).
Harousseau, J. L. et al. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005–2001 phase III trial. J. Clin. Oncol. 28, 4621–4629 (2010).
Cavo, M. et al. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet 376, 2075–2085 (2010).
Rosiñol, L. et al. Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study. Blood 120, 1589–1596 (2012).
Kumar, S. et al. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood 119, 4375–4382 (2012).
Moreau, P. et al. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N. Engl. J. Med. 374, 1621–1634 (2016).
Ghobrial, I. M. et al. Clinical profile of single-agent modified-release oprozomib tablets in patients (Pts) with hematologic malignancies: updated results from a multicenter, open-label, dose escalation phase 1b/2 study [abstract]. Blood 122, 3184 (2013).
Richardson, P. G. et al. Phase 1 study of marizomib in relapsed or relapsed and refractory multiple myeloma: NPI-0052-101 Part 1. Blood 127, 2693–2700 (2016).
The work of the authors is supported by the MD Anderson Cancer Center SPORE in Multiple Myeloma (P50 CA142509) and the MD Anderson Cancer Center Support Grant (P30 CA016672). R.Z.O., who is the Florence Maude Thomas Cancer Research Professor, would also like to acknowledge support from the National Cancer Institute (U10 CA032102, R01 CA184464 and CA194264), and thank the Brock Family Myeloma Research Fund, the Diane & John Grace Family Foundation, the Jay Solomon Myeloma Research Fund, and the Yates Ortiz Myeloma Fund.
R.Z.O. has served on advisory boards for Amgen, which developed and markets carfilzomib, and for Takeda Pharmaceuticals, which developed and markets bortezomib and ixazomib, and has received research support from these companies for clinical and laboratory projects. E.E.M. declares no competing interests.
About this article
Cite this article
Manasanch, E., Orlowski, R. Proteasome inhibitors in cancer therapy. Nat Rev Clin Oncol 14, 417–433 (2017). https://doi.org/10.1038/nrclinonc.2016.206
This article is cited by
Cell & Bioscience (2022)
World Journal of Surgical Oncology (2022)
Journal of Hematology & Oncology (2022)
Journal of Biomedical Science (2022)
Pan-cancer analysis of genomic and transcriptomic data reveals the prognostic relevance of human proteasome genes in different cancer types
BMC Cancer (2022)