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Inhibition of Heat Shock Protein 90 (HSP90)

In This Section:

HSP90 in Normal Cells

Heat shock proteins, or HSPs, are called molecular chaperones because they help maintain the stability and activity of cellular proteins by modulating their three-dimensional shapes.

A close-up view of the cytoplasm of a normal cell is shown. A dimer of two yellow proteins labeled 'HSP (Heat Shock Protein)' is present in the cytoplasm. The screen text reads, 'HSPs influence the activity and stability of cellular proteins.'

HSP90, like most heat shock proteins, acts as part of a multiprotein complex that includes other molecular chaperones. HSP90 stabilizes its so-called client proteins so they can participate more effectively in their signaling pathways. Thus, although not a signaling molecule itself, HSP90 can enhance the activity of certain signaling pathways.

A close-up view of the cytoplasm of a normal cell is shown. The yellow HSP dimer is labeled 'HSP90' and is associated with three other proteins labeled 'Chaperones.'

A close-up view of a normal cell membrane and cytoplasm is shown. The HSP90-chaperone complex is associated with a small blue protein labeled 'Client Protein.' An activated signaling pathway is shown downstream of the client protein, indicating that the chaperone complex is helping to maintain the client protein pathway in an active state. The screen text reads, 'HSP90 stabilizes its client proteins, which can enhance their signaling activity.'

HSP90 and other heat shock proteins also help stabilize cellular proteins in the presence of environmental stresses, such as increased temperatures or glucose deprivation, that can threaten cell survival.

HSP90 in Cancer Cells

Multiple myeloma cells and many other types of cancer cells have more HSP90 than normal cells. This is most likely because cancer cells must cope with numerous external and internal stressors that are not experienced by normal cells, such as low levels of oxygen or mutation of important regulatory proteins.

This is a split-screen image with a green multiple myeloma cell on the left and a pink normal cell on the right. Yellow proteins labeled 'HSP90' are visible in the cytoplasm of both cells, but significantly more HSP90 proteins are present in the multiple myeloma cell.

There is evidence that HSP90 is an integral part of the machinery that allows cancer cells to grow uncontrollably. Its client proteins are associated with processes that contribute to all of the hallmarks of cancer: growth factor independence, resistance to antigrowth signals, unlimited replicative potential, tissue invasion and metastasis, avoidance of apoptosis, and angiogenesis. Because HSP90 supports many of the biochemical mechanisms used by cancer cells to survive and grow, drugs that interfere with HSP90 may provide better cancer control than drugs that target only a single pathway.

A close-up view of a cancer cell membrane and cytoplasm is shown. The HSP90-chaperone complex is associated with a small blue protein labeled 'Client Protein.' An activated signaling pathway is shown downstream of the client protein, indicating that the chaperone complex is helping to maintain the client protein pathway in an active state.

Inhibiting HSP90

HSP90 inhibitors have been examined in preclinical models of multiple myeloma and other types of cancer. These studies have shown that HSP90 inhibitors reduce the viability of myeloma cells, even those that are resistant to standard therapies for this cancer.

A mass of green cancer cells labeled 'Multiple Myeloma Cells' is shown. Small purple dots labeled 'HSP90 Inhibitors' are shown around and in the myeloma cells.

As expected, numerous proteins and pathways are affected by HSP90 inhibitors, including many suspected to play a role in multiple myeloma. One protein affected by HSP90 inhibition is Akt. The HSP90 complex binds to and stabilizes Akt in cancer cells, allowing the protein to promote cell proliferation and survival.

A close-up view of a cancer cell membrane and cytoplasm is shown. The HSP90-chaperone complex is associated with a small blue protein labeled 'Akt.' An activated signaling pathway is shown downstream of Akt. The pathway is labeled 'Proliferation/Survival Pathway.'

However, in the presence of an HSP90 inhibitor, the interaction between HSP90 and Akt is altered. As a result, Akt becomes a target for ubiquitinylation and degradation by proteasomes, a fate shared by many other HSP90 client proteins when the activity of this molecular chaperone is inhibited.

A close-up view of a proteasome is shown. A blue protein labeled 'Akt Protein' is nearby. The Akt protein is linked to several small red circles labeled 'Ubiquitin.'

Although no HSP90 inhibitors have been approved by the FDA, several are being tested in clinical trials of multiple myeloma.

More Information

HSP90 Inhibitors

This table lists several HSP90 inhibitors that have been or are being tested in clinical trials for multiple myeloma. To date, none of these agents has been approved by the FDA for treatment of multiple myeloma. For more information on types of targeted therapies, see Understanding Targeted Therapies: An Overview.

 Research NameGeneric NameTrade Name(s)Drug Type
HSP90 InhibitorsKOS-1022 (also called 17-DMAG)Alvespimycin--Small molecule
 KOS-953 (also called 17-AAG)Tanespimycin--Small molecule
 AUY922----Small molecule


Self Test

Questions

  1. HSP90 supports cell survival by activating Akt.
    1. True
    2. False

Answers

  1. Correct Answer: b
    1. True - Incorrect.
      HSP90 does not activate Akt. Rather, the HSP90 complex stabilizes Akt. Although this increased stability makes it more likely that Akt will be activated by other signaling molecules, HSP90 cannot directly activate Akt.
    2. False - Correct.
      HSP90 does not activate Akt. Rather, the HSP90 complex stabilizes Akt. Although this increased stability makes it more likely that Akt will be activated by other signaling molecules, HSP90 cannot directly activate Akt.