Targeting Hsp90: Researchers Aim to Thwart Chaperones of the 'Guardian of the Proteome'

Jane de Lartigue, PhD
Published: Tuesday, Apr 24, 2012

Sample Hsp90 Interactions

Hsp90 Interactions

This figure illustrates some of the many channels through which Hsp90 can team up with co-chaperones to target client proteins that in turn activate hallmarks of cancer. More than 200 potential Hsp90 clients within the cell have been identified. Didier Picard, PhD, a professor in the Department of Cell Biology at the University of Geneva in Switzerland, maintains a database of Hsp90 interactors at

While p53 is often called the “guardian of the genome” for its important role in preventing the accumulation of cancer-causing DNA mutations, Hsp90 might equally be referred to as the “guardian of the proteome” (a cell’s protein complement), since it regulates the correct structure and function of many of the important proteins encoded by our DNA. Like p53, Hsp90 has become recognized as an important anticancer therapeutic target. A number of Hsp90-targeted agents are now in development.

What Is Hsp90?

Hsp90 is a member of the heat shock protein (Hsp) family, first described in 1962 as proteins induced during thermal stress. Despite the name, Hsp90 is actually active in most, if not all, cells under normal nonstress conditions; in fact, it makes up as much as 1% to 2% of total cellular protein content. Under conditions of stress (eg, lack of oxygen or nutrients, extreme temperatures), the expression of Hsp90 is further activated beyond normal levels in order to promote cell survival.

Hsps play a very important role in the cell as molecular chaperones. Once genes have been translated into proteins, they need to be folded into the correct three-dimensional structure in order to become biologically active. Hsps “chaperone” these proteins to ensure that they fold correctly and interact appropriately with other proteins. If proteins are damaged, Hsps facilitate protein refolding, or, if the damage is irreversible, they target the protein for degradation by the proteasome (the cell’s protein degradation machinery). Hsps ultimately guard the cell against the dangers of protein misfolding and aggregation.

Hsps form large multiprotein complexes with other chaperones and adaptor molecules, which aid in their function. Each Hsp has a range of different target proteins, known as clients, and exerts its chaperone activity upon these clients through cycles of binding and release, driven by the cellular energy source adenosine triphosphate (ATP).

Studies have identified more than 200 potential Hsp90 clients within the cell. Hsp90 is a particularly important chaperone in relation to cancer because many of its client proteins are cancer hallmark-causing signal transduction proteins. They include HER2, c-KIT, AKT, MET, telomerase, and the matrix metalloproteinase MMP-2.

Hsp90 is predominantly found in the cytoplasm in two different isoforms: Hsp90α (the heat shock-induced form) and Hsp90β (the constitutively active form). However, three other isoforms of Hsp90 exist in the cell. There are two isoforms localized to the endoplasmic reticulum (ER) and the mitochondria and a third membrane-bound form. Hsp90 also has been reported to be secreted into the extracellular matrix. The secreted and membrane-bound forms are thought to have important roles in angiogenesis and metastasis.

Selected Hsp90 Inhibitors Under Development

While there are currently no approved Hsp90-targeted drugs, nearly 20 agents are in clinical development, many of which are now reaching more advanced stages in a variety of different cancers. This list includes small-molecule inhibitors targeting the amino-terminal domain of Hsp90, also called the N-terminal.
Ganetespib (formerly STA-9090; Synta Pharmaceuticals Corp)
This intravenously administered molecule is currently undergoing phase IIb/III investigation in non-small cell lung cancer (NSCLC). The GALAXY trial (Ganetespib Assessment in Lung CAncer with DocetaXel) is a randomized, international study evaluating docetaxel versus ganetespib plus docetaxel in patients with stage IIIb or IV NSCLC.

The drug also is being tested in patients with metastatic hormone-resistant prostate cancer, solid tumors, myeloproliferative disorders, and esophagogastric cancer, among others. Interim data from clinical trials indicate that ganetespib shows promise in the treatment of lung cancer and solid tumors; in a phase I, open-label, dose-escalation study of twice-weekly ganetespib in 36 patients with metastatic solid tumors, there was one partial response and 10 incidences of stable disease, and it was well tolerated. identifiers: NCT01348126; NCT01270880; NCT01183364; NCT00858572; NCT01167114; NCT00688116
Retaspimycin hydrochloride (IPI-504; Infinity Pharmaceuticals)
Also intravenously administered, retaspimycin hydrochloride is currently in phase II trials in combination with docetaxel in patients with NSCLC, and in a phase II trial of patients with previously treated NSCLC. It is also being studied in combination with everolimus in patients with KRAS-mutant NSCLC.

NCT01362400; NCT01427946
NVP-AUY922 (Novartis)
This agent is undergoing investigation in phase I/II trials in patients with NSCLC, HER2- positive advanced breast cancer, gastric cancer, and gastrointestinal stromal tumor (GIST). It is also being studied alone and in combination with trastuzumab in HER2-positive breast cancer and with the proteasomal inhibitor bortezomib in patients with multiple myeloma. In a phase I dose-escalation study, 14% of patients experienced prolonged disease stabilization. It also is administered intravenously.

NCT01124864; NCT01404650; NCT01402401
KW-2478 (Kyowa Hakko Kirin Pharma, Inc)
Phase I/II trials are underway to evaluate the drug in combination with bortezomib in patients with relapsed or refractory multiple myeloma.

BIIB021 (Biogen Idec)
This agent is an orally administered drug that recently completed phase II testing in patients with GIST, and in combination with exemestane in patients with hormone receptor-positive metastatic breast cancer.

NCT00618319; NCT01004081
BIIB028 (Biogen Idec)
This intravenously administered version recently completed phase I testing in patients with advanced solid tumors.

Debio 0932 (Debiopharm)
Formerly CUDC305 (Curis), the orally administered, small molecule is in phase I trials in patients with advanced solid tumors or lymphoma.

NVP-HSP990 (Novartis)
This orally administered version of the inhibitor is undergoing phase I clinical testing in patients with advanced solid tumors.

MPC-3100 (Myrexis, Inc)
Also an orally administered small molecule, MPC-3100 recently completed phase I testing in patients with relapsed or refractory cancer. MPC-3100 also served as parent molecule in the development of MPC-0767, which has better solubility and is more easily formulated. MPC- 0767 is undergoing preclinical testing.


Cancer Hijacks the Chaperones

The important chaperone function of Hsp90 is hijacked during cancer, so that mutated and overexpressed proteins are protected from misfolding and degradation. This promotes cancer survival in its stressful environment and promotes the ability of cancer cells to tolerate the many genetic alterations associated with cancer.

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