Journal
CANCERS
Volume 11, Issue 1, Pages -Publisher
MDPI
DOI: 10.3390/cancers11010066
Keywords
proteotoxic stress; chemoresistance; proteasome; unfolded protein response; autophagy; multiple myeloma; triple negative breast cancer; protein quality control
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Funding
- UCD Wellcome Institutional Strategic Support Fund - University College Dublin
- UCD Wellcome Institutional Strategic Support Fund - SFI-HRB-Wellcome Biomedical Research Partnership [204844/Z/16/Z]
- Mater Foundation
- Mater Misericordiae University Hospital (MMUH) Dublin Ireland
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Despite significant advances in cancer diagnostics and therapeutics the majority of cancer unfortunately remains incurable, which has led to continued research to better understand its exceptionally diverse biology. As a result of genomic instability, cancer cells typically have elevated proteotoxic stress. Recent appreciation of this functional link between the two secondary hallmarks of cancer: aneuploidy (oxidative stress) and proteotoxic stress, has therefore led to the development of new anticancer therapies targeting this emerging Achilles heel of malignancy. This review highlights the importance of managing proteotoxic stress for cancer cell survival and provides an overview of the integral role proteostasis pathways play in the maintenance of protein homeostasis. We further review the efforts undertaken to exploit proteotoxic stress in multiple myeloma (as an example of a hematologic malignancy) and triple negative breast cancer (as an example of a solid tumor), and give examples of: (1) FDA-approved therapies in routine clinical use; and (2) promising therapies currently in clinical trials. Finally, we provide new insights gleaned from the use of emerging technologies to disrupt the protein secretory pathway and repurpose E3 ligases to achieve targeted protein degradation.
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