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Lessons Learned from Proteasome Inhibitors, the Paradigm for Targeting Protein Homeostasis in Cancer

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HSF1 and Molecular Chaperones in Biology and Cancer

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1243))

Abstract

Targeting aberrant protein homeostasis (proteostasis) in cancer is an attractive therapeutic strategy. However, this approach has thus far proven difficult to bring to clinical practice, with one major exception: proteasome inhibition. These small molecules have dramatically transformed outcomes for patients with the blood cancer multiple myeloma. However, these agents have failed to make an impact in more common solid tumors. Major questions remain about whether this therapeutic strategy can be extended to benefit even more patients. Here we discuss the role of the proteasome in normal and tumor cells, the basic, preclinical, and clinical development of proteasome inhibitors, and mechanisms proposed to govern both intrinsic and acquired resistance to these drugs. Years of study of both the mechanism of action and modes of resistance to proteasome inhibitors reveal these processes to be surprisingly complex. Here, we attempt to draw lessons from experience with proteasome inhibitors that may be relevant for other compounds targeting proteostasis in cancer, as well as extending the reach of proteasome inhibitors beyond blood cancers.

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Acknowledgements

A.P.W. would like to acknowledge research support from the Multiple Myeloma Research Foundation, Gabrielle’s Angels Foundation for Cancer Research, Helen Diller Family Comprehensive Cancer Center at UCSF, and NIH grants K08 CA184116 and R01 CA226851 for supporting related work in his laboratory.

Disclosures

A.P.W. is a member of the scientific advisory board and equity holder in Indapta Therapeutics and Protocol Intelligence. A.P.W. has received past research funding from TeneoBio, Sutro BioPharma, and Quadriga Biosciences.

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Authors and Affiliations

  1. Department of Medicine, Division of Hematology/Oncology, University of California, San Francisco, CA, USA

    Swetha Kambhampati

  2. Department of Laboratory Medicine, University of California, San Francisco, CA, USA

    Arun P. Wiita

  3. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA

    Arun P. Wiita

Authors
  1. Swetha Kambhampati
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  2. Arun P. Wiita
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Correspondence to Arun P. Wiita .

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  1. Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Marc Laurence Mendillo

  2. University of Chicago, Chicago, IL, USA

    David Pincus

  3. Weizmann Institute of Science, Rehovot, Israel

    Ruth Scherz-Shouval

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Kambhampati, S., Wiita, A.P. (2020). Lessons Learned from Proteasome Inhibitors, the Paradigm for Targeting Protein Homeostasis in Cancer. In: Mendillo, M.L., Pincus, D., Scherz-Shouval, R. (eds) HSF1 and Molecular Chaperones in Biology and Cancer. Advances in Experimental Medicine and Biology, vol 1243. Springer, Cham. https://doi.org/10.1007/978-3-030-40204-4_10

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