Heat shock protein 90 inhibition in lung cancer.
The heat shock protein 90 (Hsp90) chaperone is required for the conformational maturation and stability of multiple oncogenic kinases that drive signal transduction and proliferation of lung cancer cells. The recent demonstration that mutant epidermal growth factor receptor is an Hsp90 client, irrespective of the presence of the secondary threonine-to-methionine amino acid substitution mutation at position 790 mediating anilinoquinazoline resistance, suggests Hsp90 inhibition as a novel strategy against this group of lung cancers. The rarer epidermal growth factor receptors harboring exon 20 insertions and vIII mutations are also Hsp90 clients. Lung cancers may also be driven by mutant ErbB2, mutant B-Raf, or mutant or overexpressed c-Met, all of which are also degraded on Hsp90 inhibition. Hsp90 inhibitors may be synergistic with other drugs that disrupt chaperone function, including inhibitors of histone deacetylase 6 and the proteasome and agents that inhibit Hsp70 function. Hsp90 plays a unique antiapoptotic role in small cell lung cancer cells, so that Hsp90 inhibition results in substantial cell death in both chemosensitive and chemoresistant small cell lung cancer cell lines. Clinically, the geldanamycin compounds are the most mature, with manageable toxic effects. Several new classes of Hsp90 inhibitors are emerging, including purines and pyrazoles that have entered phase 1 trials. The available data suggest that Hsp90 inhibitors should be evaluated in multiple lung cancer subsets.
Department of Medicine, Brigham and Women's Hospital and Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Takeshi
T
Shimamura
Geoffrey I
GI
Shapiro
D016227:Benzoquinones / Q000008:administration & dosage*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000556:secondary; D045744:Cell Line, Tumor / Q000187:drug effects; D017321:Clinical Trials, Phase I as Topic; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D005500:Follow-Up Studies; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000008:administration & dosage*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D018570:Risk Assessment; D016019:Survival Analysis; D016896:Treatment Outcome
D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D066246:ErbB Receptors; C001277:geldanamycin