title: Combined inhibition of Wee1 and Hsp90 activates intrinsic apoptosis in cancer cells.
abstract: Heat shock protein 90 (Hsp90) is an essential, evolutionarily conserved molecular chaperone. Cancer cells rely on Hsp90 to chaperone mutated and/or activated oncoproteins, and its involvement in numerous signaling pathways makes it an attractive target for drug development. Surprisingly, however, the impact of Hsp90 inhibitors on cancer cells is frequently cytostatic in nature, and efforts to enhance the antitumor activity of Hsp90 inhibitors in the clinic remain a significant challenge. In agreement with previous data obtained using Wee1 siRNA, we show that dual pharmacologic inhibition of Wee1 tyrosine kinase and Hsp90 causes cancer cells to undergo apoptosis in vitro and in vivo. Gene expression profiling revealed that induction of the intrinsic apoptotic pathway by this drug combination coincided with transcriptional downregulation of Survivin and Wee1, an outcome not seen in cells treated separately with either agent. At the translational level, expression of these two proteins, as well as activated Akt, was completely abrogated. These data support the hypothesis that Wee1 inhibition sensitizes cancer cells to Hsp90 inhibitors; they establish combined Wee1/Hsp90 inhibition as a novel therapeutic strategy; and they provide a mechanistic rationale for enhancing the pro-apoptotic activity of Hsp90 inhibitors.
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Aki
authors.initials: A
authors.lastname: Iwai
authors.forename: Dimitra
authors.initials: D
authors.lastname: Bourboulia
authors.forename: Mehdi
authors.initials: M
authors.lastname: Mollapour
authors.forename: Sandra
authors.initials: S
authors.lastname: Jensen-Taubman
authors.forename: Sunmin
authors.initials: S
authors.lastname: Lee
authors.forename: Alison C
authors.initials: AC
authors.lastname: Donnelly
authors.forename: Soichiro
authors.initials: S
authors.lastname: Yoshida
authors.forename: Naoto
authors.initials: N
authors.lastname: Miyajima
authors.forename: Shinji
authors.initials: S
authors.lastname: Tsutsumi
authors.forename: Armine K
authors.initials: AK
authors.lastname: Smith
authors.forename: David
authors.initials: D
authors.lastname: Sun
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Wu
authors.forename: Brian S
authors.initials: BS
authors.lastname: Blagg
authors.forename: Jane B
authors.initials: JB
authors.lastname: Trepel
authors.forename: William G
authors.initials: WG
authors.lastname: Stetler-Stevenson
authors.forename: Len
authors.initials: L
authors.lastname: Neckers
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D017353:Gene Deletion; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008297:Male; D051379:Mice; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays
chemical_list: D016227:Benzoquinones; D018797:Cell Cycle Proteins; C074510:HSP82 protein, S cerevisiae; D018841:HSP90 Heat-Shock Proteins; C112969:HSP90AA1 protein, human; D047029:Lactams, Macrocyclic; D009687:Nuclear Proteins; D029701:Saccharomyces cerevisiae Proteins; C112765:tanespimycin; C099685:SWE1 protein, S cerevisiae; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human