title: The HSP90 inhibitor NVP-AUY922 potently inhibits non-small cell lung cancer growth.
abstract: Heat shock protein 90 (HSP90) is involved in protein folding and functions as a chaperone for numerous client proteins, many of which are important in non-small cell lung cancer (NSCLC) pathogenesis. We sought to define preclinical effects of the HSP90 inhibitor NVP-AUY922 and identify predictors of response. We assessed in vitro effects of NVP-AUY922 on proliferation and protein expression in NSCLC cell lines. We evaluated gene expression changes induced by NVP-AUY922 exposure. Xenograft models were evaluated for tumor control and biological effects. NVP-AUY922 potently inhibited in vitro growth in all 41 NSCLC cell lines evaluated with IC50 < 100 nmol/L. IC100 (complete inhibition of proliferation) < 40 nmol/L was seen in 36 of 41 lines. Consistent gene expression changes after NVP-AUY922 exposure involved a wide range of cellular functions, including consistently decreased dihydrofolate reductase after exposure. NVP-AUY922 slowed growth of A549 (KRAS-mutant) xenografts and achieved tumor stability and decreased EGF receptor (EGFR) protein expression in H1975 xenografts, a model harboring a sensitizing and a resistance mutation for EGFR-tyrosine kinase inhibitors in the EGFR gene. These data will help inform the evaluation of correlative data from a recently completed phase II NSCLC trial and a planned phase IB trial of NVP-AUY922 in combination with pemetrexed in NSCLCs.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA. egaron@mednet.ucla.edu
authors.forename: Edward B
authors.initials: EB
authors.lastname: Garon
authors.forename: Richard S
authors.initials: RS
authors.lastname: Finn
authors.forename: Habib
authors.initials: H
authors.lastname: Hamidi
authors.forename: Judy
authors.initials: J
authors.lastname: Dering
authors.forename: Sharon
authors.initials: S
authors.lastname: Pitts
authors.forename: Naeimeh
authors.initials: N
authors.lastname: Kamranpour
authors.forename: Amrita J
authors.initials: AJ
authors.lastname: Desai
authors.forename: Wylie
authors.initials: W
authors.lastname: Hosmer
authors.forename: Susan
authors.initials: S
authors.lastname: Ide
authors.forename: Emin
authors.initials: E
authors.lastname: Avsar
authors.forename: Michael Rugaard
authors.initials: MR
authors.lastname: Jensen
authors.forename: Cornelia
authors.initials: C
authors.lastname: Quadt
authors.forename: Manway
authors.initials: M
authors.lastname: Liu
authors.forename: Steven M
authors.initials: SM
authors.lastname: Dubinett
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Slamon
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002986:Clinical Trials as Topic; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000008:administration & dosage*; D018832:Molecular Chaperones / Q000008:administration & dosage; D012118:Resorcinols / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D018832:Molecular Chaperones; D012118:Resorcinols; D066246:ErbB Receptors