Chaperoning oncogenes: Hsp90 as a target of geldanamycin.
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, and/or over-expressed signaling proteins, that promote cancer cell growth and/or survival. 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 anti-tumor activity in preclinical model systems. One Hsp90 inhibitor, 17-AAG, has completed Phase I clinical trial and several Phase II trials of this agent are in progress. Hsp90 inhibitors are unique in that, although they are directed toward a specific molecular target, they simultaneously inhibit multiple signaling pathways that frequently interact to promote cancer cell survival. Further, by inhibiting nodal points in multiple overlapping survival pathways utilized by cancer cells, a combination of an Hsp90 inhibitor with standard chemotherapeutic agents may dramatically increase the in vivo efficacy of the standard agent. 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 be effective toward multiple forms of cancer.
Neckers
L
L
Urologic Oncology Branch, National Cancer Institute, Rockville MD, 20850, USA. len@helix.nih.gov
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D016227:Benzoquinones; D004721:Endoplasmic Reticulum / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D047029:Lactams, Macrocyclic; D009857:Oncogenes; D011809:Quinones / Q000494:pharmacology*
D020533:Angiogenesis Inhibitors; D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; C497442:HIF1A protein, human; D018841:HSP90 Heat-Shock Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047029:Lactams, Macrocyclic; D011809:Quinones; C001277:geldanamycin