Targeting the dynamic HSP90 complex in cancer

Key Points

  • Heat shock protein 90 (HSP90) is a molecular chaperone of numerous oncoproteins. Therefore, cancer cells can be considered to be 'addicted' to this molecule.

  • HSP90 is also a mediator of cellular homeostasis. As such, it facilitates numerous transient low-affinity protein–protein interactions that have only recently been identified using bioinformatic and proteomic techniques.

  • Although primarily a cytoplasmic protein, HSP90 affects diverse nuclear processes, including transcription, chromatin remodelling and DNA damage-induced mutation.

  • HSP90 is a conformationally dynamic protein. ATP binding to the amino (N) domain and its subsequent hydrolysis by HSP90 drive a conformational cycle that is essential for chaperone activity.

  • In eukaryotes, co-chaperones and post-translational modifications regulate both client interactions with HSP90 and HSP90 ATPase activity.

  • Co-chaperones and post-translational modifications can also affect the efficacy of HSP90 inhibitors.

  • HSP90 inhibitors currently under clinical evaluation interact with the N domain ATP-binding pocket, prevent ATP binding, and stop the chaperone cycle, leading to client protein degradation.

  • Because of the HSP90 client repertoire, HSP90 inhibitors may combat oncogene switching, which is an important mechanism of tumour escape from tyrosine kinase inhibitors.

  • Derivatives of the coumarin antibiotic novobiocin represent an alternative strategy for inhibiting HSP90 by targeting a unique carboxy-terminal (C) domain.

  • Optimal development of HSP90-directed therapeutics will depend on synthesizing information gained from careful genetic analysis of primary and metastatic tumours with an understanding of the unique environmental context in which the tumour is thriving at the expense of the host.

Abstract

The molecular chaperone heat shock protein 90 (HSP90) has been used by cancer cells to facilitate the function of numerous oncoproteins, and it can be argued that cancer cells are 'addicted' to HSP90. However, although recent reports of the early clinical efficacy of HSP90 inhibitors are encouraging, the optimal use of HSP90-targeted therapeutics will depend on understanding the complexity of HSP90 regulation and the degree to which HSP90 participates in both neoplastic and normal cellular physiology.

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Figure 1: The HSP90 chaperone cycle.
Figure 2: Co-chaperones and post-translational modifications modulate HSP90 chaperone activity.
Figure 3: HSP90 modulates nuclear events.

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Acknowledgements

The authors would like to thank K. Beebe, Y. S. Kim, and all members of the Neckers and Trepel laboratories for their helpful comments.

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Correspondence to Len Neckers.

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The authors declare no competing financial interests.

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ClinicalTrials.gov

NCT00093496

NCT00431015

NCT00514371

NCT00526045

NCT00708292

NCT00964873

NCT01031225

NCT01063907

NCT01081600

NCT01081613

National Cancer Institute Drug Dictionary

bortezomib

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Glossary

Co-chaperone

Protein that assists or alters the function of other chaperones.

Oncogene addiction

The hypothesis that tumours arising as a result of a particular oncogenic lesion are dependent on the continued expression of that oncogene.

Kinetochore

Specialized assembly of proteins that binds to a region of the chromosome called the centromere and is essential for chromosome segregation during eukaryotic cell division.

Apoptosome

A caspase-activating complex that is formed when cytochrome c is released from mitochondria. It initiates oligomerization of APAF1, which binds procaspase-9 and thereby initiates the caspase cascade that leads to programmed cell death.

S-nitrosylation

The covalent attachment of a nitrogen monoxide group to the thiol side chain of cysteine.

Proteotoxic stress

Protein damage caused by physical or chemical agents such as heat, heavy metals, hypoxia and some anticancer drugs.

DNA polymerase-η

A member of the DNA polymerase Y family, a group of low-fidelity DNA polymerases that can replicate through damaged DNA.

Transposon

Mobile genetic element that can insert in different positions in the genome and cause mutations.

Piwi-interacting RNA (piRNA)

A class of germline-specific small RNA molecule that suppresses transposon mobility by RNA silencing.

Castrate-resistant prostate cancer

Prostate cancer that no longer responds to androgen deprivation therapy.

Prostate-specific antigen (PSA)

A protein produced by the prostate that is increased in the blood of men with prostate cancer, benign prostatic hyperplasia, or infection and inflammation of the prostate.

Pharmacodynamic

The relationship between drug concentration (pharmacokinetics) and its biological effects (what the drug does to the body).

Trastuzumab

A humanized monoclonal antibody that binds HER2 on tumour cells and prevents uncontrolled proliferation caused by aberrant HER2 signalling.

RECIST

A set of published rules that define when cancer patients improve ('respond'), stay the same ('stable') or worsen ('progression') during treatments.

Triple-negative breast cancer

Breast cancer that lacks expression of oestrogen, progesterone and HER2 receptors.

Neuropathy

Refers to any disease or injury affecting nerves or nerve cells.

Graft-versus-host disease

A common complication of allogeneic bone marrow transplantation in which functional immune cells in the transplanted marrow recognize the recipient as foreign and mount an immunological attack.

Alloreactive T cell

White blood cell that recognizes a complex composed of a major histocompatibility complex (MHC) molecule and a peptide in which the MHC or peptide are derived from a genetically different member of the same species.

FDG-PET

A radio-labelled imaging methodology for detecting cancers that relies on increased glucose uptake by the tumour — a characteristic of cancers and other pathologies.

Proton magnetic resonance

The resonance of protons to radiation in a magnetic field. Proton magnetic resonance spectra yield a great deal of information about molecular structure as most organic molecules contain hydrogen atoms that absorb energy of different wavelengths depending on their bonding environment.

Non-ansamycin HSP90 inhibitor

HSP90 inhibitor lacking the benzoquinone ansamycin backbone found in tanespimycin (17-AAG), alvespimycin (17-DMAG) and retaspimycin (IPI-504).

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Trepel, J., Mollapour, M., Giaccone, G. et al. Targeting the dynamic HSP90 complex in cancer. Nat Rev Cancer 10, 537–549 (2010). https://doi.org/10.1038/nrc2887

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