title: Antitumor activity of SNX-2112, a synthetic heat shock protein-90 inhibitor, in MET-amplified tumor cells with or without resistance to selective MET Inhibition.
abstract: OBJECTIVE
  Heat shock protein-90 (HSP-90), a molecular chaperone required by numerous oncogenic kinases [e.g., HER-2, epidermal growth factor receptor (EGFR), Raf-1, v-Src, and AKT] for conformational stability, has attracted wide interest as a novel target for cancer therapy. HSP-90 inhibition induces degradation of HSP-90 client proteins, leading to a combinatorial inhibition of multiple oncogenic signaling pathways with consecutive growth arrest and apoptosis. MET, a tyrosine kinase that is constitutively active in tumor cells with MET oncogene amplification, has recently been identified as another HSP-90 client.
  
  
  METHODS
  The aim of our study was to assess the efficacy of SNX-2112, a synthetic HSP-90 inhibitor, in 3 different MET-amplified tumor cell lines (GTL-16, MKN-45, and EBC-1) as well as PR-GTL-16 cells, a GTL-16 subline selected for resistance to the highly selective MET kinase inhibitor PHA-665752.
  
  
  RESULTS
  In all cell lines, SNX-2112 led to degradation of MET, HER-2, EGFR, and AKT, as well as abrogation of Ras/Raf/MEK/MAPK and PI3K/AKT signaling, followed by complete cell cycle arrest. SNX-5542, an orally bioavailable prodrug of SNX-2112, displayed significant antitumor efficacy in vivo in nude mice bearing MET-amplified tumor xenografts. Importantly, HSP-90 inhibition maintained its antitumor efficacy in PR-GTL-16 cells both in vitro and in vivo, suggesting that HSP-90 inhibition could be a particularly valuable strategy in MET-amplified tumors that have acquired resistance to MET kinase inhibition.
  
  
  CONCLUSIONS
  Our study provides evidence for the efficacy of HSP-90 inhibition in MET-amplified cancer cells, particularly when MET kinase inhibitor resistance has emerged.
authors.affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bachleitner-Hofmann
authors.forename: Mark Y
authors.initials: MY
authors.lastname: Sun
authors.forename: Chin-Tung
authors.initials: CT
authors.lastname: Chen
authors.forename: David
authors.initials: D
authors.lastname: Liska
authors.forename: Zhaoshi
authors.initials: Z
authors.lastname: Zeng
authors.forename: Agnes
authors.initials: A
authors.lastname: Viale
authors.forename: Adam B
authors.initials: AB
authors.lastname: Olshen
authors.forename: Martina
authors.initials: M
authors.lastname: Mittlboeck
authors.forename: James G
authors.initials: JG
authors.lastname: Christensen
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
authors.forename: David B
authors.initials: DB
authors.lastname: Solit
authors.forename: Martin R
authors.initials: MR
authors.lastname: Weiser
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000494:pharmacology
chemical_list: C480541:5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one; D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D006576:Heterocyclic Compounds, 4 or More Rings; D007211:Indoles; D047428:Protein Kinase Inhibitors; C534922:SNX 2112; D013450:Sulfones; D019859:Proto-Oncogene Proteins c-met