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Published on: December 18, 2013
Lessons Learned from Proteasome Inhibitors, the Paradigm for Targeting Protein Homeostasis in Cancer
Swetha Kambhampati1, Arun P Wiita2,3
1Department of Medicine, Division of Hematology/Oncology, University of California, San Francisco, CA, USA.
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.
Insights
Proteasome inhibitors are effective against multiple myeloma but not solid tumors. Further research aims to expand their use in cancer therapy by understanding complex resistance mechanisms.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Targeting protein homeostasis (proteostasis) is a key cancer therapeutic strategy.
- Proteasome inhibition has shown success in multiple myeloma but limited efficacy in solid tumors.
- Understanding resistance mechanisms is crucial for expanding proteasome inhibitor applications.
Purpose of the Study:
- To review the role of the proteasome in normal and cancer cells.
- To discuss the development and mechanisms of proteasome inhibitors.
- To explore strategies for overcoming resistance and extending proteasome inhibitor efficacy to solid tumors.
Main Methods:
- Literature review of basic, preclinical, and clinical studies on proteasome inhibitors.
- Analysis of proteasome function in normal and tumor cells.
- Examination of intrinsic and acquired resistance mechanisms.
Main Results:
- Proteasome inhibitors have revolutionized multiple myeloma treatment.
- Significant challenges remain in applying proteasome inhibitors to solid tumors.
- Complexities in proteasome inhibitor action and resistance are highlighted.
Conclusions:
- Lessons learned from proteasome inhibitors may inform other proteostasis-targeting drugs.
- Strategies are needed to overcome resistance and broaden the clinical utility of proteasome inhibitors.
- Extending proteasome inhibitor benefits beyond hematological malignancies is a critical goal.
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