Kuhn and colleagues report on the novel strategy of targeting the immunoproteasome to overcome bortezomib resistance on the one hand, and avoid side effects on the other. The core proteasome (20S) protease complex is composed of α and β subunits; the β1, β2, and β5 subunits mediate caspase-like (C-L), trypsin-like (T-L), and chymotrypsin-like (CT-L) activities. The corresponding interferon-inducible subunits of the proteasome are the β1i, β2i, and β5i subunits of the immunoproteasome, which enhance the generation of antigenic peptides for MHC Class I presentation. In this study PSI-001, a selective inhibitor of β1i, is shown to overcome resistance to proteasome inhibitor bortezomib in preclinical models. Moreover, the data suggest that neuropathy may not be induced by this more selective β1i inhibitor, providing the framework for clinical trials of selective immunoproteasome inhibitors to improve outcome and lessen toxicity in multiple myeloma (MM).

Proteasome inhibition has achieved remarkable anti-tumor activity and can overcome cell adhesion-mediated drug resistance to conventional therapies in both in vitro and in vivo models of MM cells in the bone marrow microenvironment.1,2  Moreover, remarkable extent and frequency of response in MM were observed in phase I clinical trials.3  Based upon durable responses with associated clinical benefit in patients with relapsed refractory,4  relapsed,5  and newly diagnosed6  MM, bortezomib was FDA-approved for treatment in these settings in 2003, 2005, and 2008, respectively. However, its use is associated with neuropathy and thrombocytopenia. Moreover, not all patients respond, and those that do eventually develop resistance. Acquired mutations in proteasome subunits have been associated with bortezomib resistance.7  Carfilzomib and CEP-18770 both more potently inhibit the CT-L activity, as does bortezomib, whereas NPI0052 inhibits the CT-L activity as well as the T-L and C-L activities.8,9  All can overcome bortezomib resistance in preclinical studies and are undergoing clinical evaluation. Alternatively, heat shock protein 90 inhibitors,10  Akt inhibitors,11  and histone deacetylase inhibitors12-14  have each been combined with bortezomib to overcome bortezomib resistance in preclinical and early-phase clinical trials; these combinations are each now undergoing evaluation in randomized phase III clinical trials for FDA registration. Finally, we have shown in preclinical models that combinations of proteasome inhibitors bortezomib and NPI0052, even at doses which are ineffective alone, can achieve synergistic cytotoxicity with a very favorable side effect profile.15 

In Brief

Of note, carfilzomib, CEP-18770, and NPI0052 all inhibit both constitutive and immunoproteasome activities; and we have shown that bortezomib inhibits β5 and β1 constitutive as well as immunoproteasome subunit activities to a similar extent in MM cells.16  Therefore, whether the more selective inhibition of immunoproteasome activity, as reported here, will overcome clinical bortezomib resistance remains to be determined. Importantly, immunoproteasomes are restricted to hematologic cells, suggesting a more favorable therapeutic index than these inhibitors of the constitutive proteasome activities. However, whether inhibition of the immunoproteasome confers immunosuppression needs to be a particular focus of clinical trials. Importantly, fluorogenic substrates are now available to evaluate both the constitutive and immunoproteasome subunit activities17  in MM cells before and after treatment to correlate the extent of qualitative and quantitative inhibition of the constitutive versus immunoproteasome activity with tumor response versus side effect profile. These studies will provide the rationale for next-generation, more potent and less toxic, single-agent or combination inhibitor approaches, thereby expanding the spectrum of patients benefiting from proteasome inhibitor therapeutic strategies.

References

References
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LeBlanc R, Catley LP, Hideshima T, et al. Proteasome inhibitor PS-341 inhibits human myeloma cell growth in vivo and prolongs survival in a murine model. Cancer Res. 2002;62:4996-5000.
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Orlowski RZ, Stinchcombe TE, Mitchell BS, et al. Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol. 2002;20:4420-7.
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Mitsiades N, Mitsiades CS, Poulaki V, et al. Molecular sequelae of proteasome inhibition in human multiple myeloma cells. Proc Natl Acad Sci USA. 2002;99:14374-9.
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Mitsiades CS, Mitsiades NS, McMullan CJ, et al. Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications. Proc Natl Acad Sci USA. 2004;101:540-5.
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Hideshima T, Bradner JE, Wong J, et al. Small-molecule inhibition of proteasome and aggresome function induces synergistic anti-tumor activity in multiple myeloma. Proc Natl Acad Sci USA. 2005;102:8567-72.
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Altun M, Galardy P, Shringapure R, et al. Effects of PS-341 on the activity and composition of proteasomes in multiple myeloma cells. Cancer Res. 2005;65:7896-901.

Competing Interests

Dr. Anderson indicated no relevant conflicts of interest.