Proteasome inhibitors in cancer therapy

Key Points

  • 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

Abstract

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.

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Figure 1: Balance between proteasomal load and capacity.

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Acknowledgements

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.

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Correspondence to Robert Z. Orlowski.

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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.

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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

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