Heat shock protein 90.
OBJECTIVE
Heat shock protein 90 (Hsp90) is a molecular chaperone required for the stability and function of a number of conditionally activated and/or expressed signaling proteins, as well as multiple mutated, chimeric, or overexpressed signaling proteins, which promote cancer cell growth or survival or both. Hsp90 inhibitors, by interacting specifically with a single molecular target, cause the inactivation, destabilization, and eventual degradation of Hsp90 client proteins, and they have shown promising antitumor activity in preclinical model systems. One Hsp90 inhibitor, 17-AAG, has completed Phase I clinical trial, and several Phase II trials are in progress. Hsp90 inhibitors are unique in that, although they are directed towards a specific molecular target, they simultaneously inhibit multiple signaling pathways that frequently interact to promote cancer cell survival.


RESULTS
Recently identified clients of Hsp90 participate, frequently in overlapping pathways, in mediating cancer cell survival. These include Akt, Her2, and HIF-1 alpha. Thus, by inhibiting multiple survival pathways used by cancer cells, combination of an Hsp90 inhibitor with standard chemotherapeutic agents may dramatically increase the in vivo efficacy of the standard agent. Furthermore, Hsp90 modulates androgen receptor activity and the activity of several mutated kinases characteristic of several leukemias and lymphomas, making Hsp90 inhibition an attractive modality in these cases.


CONCLUSIONS
Hsp90 inhibitors may circumvent the characteristic genetic plasticity that has allowed cancer cells to eventually evade the toxic effects of most molecularly targeted agents. The mechanism-based use of Hsp90 inhibitors, both alone and in combination with other drugs, should augment the treatment of multiple forms of cancer.
Neckers
Len
L
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Rockville, Maryland 20850, USA. len@helix.nih.gov
Ivy
S Percy
SP
D014408:Biomarkers, Tumor / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D017321:Clinical Trials, Phase I as Topic; D018734:Genes, erbB-2 / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000627:therapeutic use*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011944:Receptors, Androgen / Q000187:drug effects / Q000378:metabolism; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects / Q000378:metabolism
D014408:Biomarkers, Tumor; C497442:HIF1A protein, human; D018841:HSP90 Heat-Shock Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011518:Proto-Oncogene Proteins; D011944:Receptors, Androgen; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt