title: Affinity-based proteomics reveal cancer-specific networks coordinated by Hsp90.
abstract: Most cancers are characterized by multiple molecular alterations, but identification of the key proteins involved in these signaling pathways is currently beyond reach. We show that the inhibitor PU-H71 preferentially targets tumor-enriched Hsp90 complexes and affinity captures Hsp90-dependent oncogenic client proteins. We have used PU-H71 affinity capture to design a proteomic approach that, when combined with bioinformatic pathway analysis, identifies dysregulated signaling networks and key oncoproteins in chronic myeloid leukemia. The identified interactome overlaps with the well-characterized altered proteome in this cancer, indicating that this method can provide global insights into the biology of individual tumors, including primary patient specimens. In addition, we show that this approach can be used to identify previously uncharacterized oncoproteins and mechanisms, potentially leading to new targeted therapies. We further show that the abundance of the PU-H71-enriched Hsp90 species, which is not dictated by Hsp90 expression alone, is predictive of the cell's sensitivity to Hsp90 inhibition.
authors.affiliation: Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, New York, USA.
authors.forename: Kamalika
authors.initials: K
authors.lastname: Moulick
authors.forename: James H
authors.initials: JH
authors.lastname: Ahn
authors.forename: Hongliang
authors.initials: H
authors.lastname: Zong
authors.forename: Anna
authors.initials: A
authors.lastname: Rodina
authors.forename: Leandro
authors.initials: L
authors.lastname: Cerchietti
authors.forename: Erica M
authors.initials: EM
authors.lastname: Gomes DaGama
authors.forename: Eloisi
authors.initials: E
authors.lastname: Caldas-Lopes
authors.forename: Kristin
authors.initials: K
authors.lastname: Beebe
authors.forename: Fabiana
authors.initials: F
authors.lastname: Perna
authors.forename: Katerina
authors.initials: K
authors.lastname: Hatzi
authors.forename: Ly P
authors.initials: LP
authors.lastname: Vu
authors.forename: Xinyang
authors.initials: X
authors.lastname: Zhao
authors.forename: Danuta
authors.initials: D
authors.lastname: Zatorska
authors.forename: Tony
authors.initials: T
authors.lastname: Taldone
authors.forename: Peter
authors.initials: P
authors.lastname: Smith-Jones
authors.forename: Mary
authors.initials: M
authors.lastname: Alpaugh
authors.forename: Steven S
authors.initials: SS
authors.lastname: Gross
authors.forename: Nagavarakishore
authors.initials: N
authors.lastname: Pillarsetty
authors.forename: Thomas
authors.initials: T
authors.lastname: Ku
authors.forename: Jason S
authors.initials: JS
authors.lastname: Lewis
authors.forename: Steven M
authors.initials: SM
authors.lastname: Larson
authors.forename: Ross
authors.initials: R
authors.lastname: Levine
authors.forename: Hediye
authors.initials: H
authors.lastname: Erdjument-Bromage
authors.forename: Monica L
authors.initials: ML
authors.lastname: Guzman
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Nimer
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
authors.forename: Len
authors.initials: L
authors.lastname: Neckers
authors.forename: Gabriela
authors.initials: G
authors.lastname: Chiosis
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D052117:Benzodioxoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D019295:Computational Biology; D055808:Drug Discovery; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology*; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D040901:Proteomics / Q000379:methods*; D011687:Purines / Q000494:pharmacology; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D052117:Benzodioxoles; D018841:HSP90 Heat-Shock Proteins; D011687:Purines; C526550:9H-purine-9-propanamine, 6-amino-8-((6-iodo-1,3-benzodioxol-5-yl)thio)-N-(1-methylethyl)-