title: Inhibiting heat shock protein 90 (HSP90) limits the formation of liver cysts induced by conditional deletion of Pkd1 in mice.
abstract: Polycystic liver disease (PLD) occurs in 75-90% of patients affected by autosomal dominant polycystic kidney disease (ADPKD), which affects 1∶400-1,000 adults and arises from inherited mutations in the PKD1 or PKD2 genes. PLD can lead to bile duct obstructions, infected or bleeding cysts, and hepatomegaly, which can diminish quality of life. At present, no effective, approved therapy exists for ADPKD or PLD. We recently showed that inhibition of the molecular chaperone heat shock protein 90 (HSP90) with a small molecule inhibitor, STA-2842, induced the degradation of multiple HSP90-dependent client proteins that contribute to ADPKD pathogenesis and slowed the progression of renal cystogenesis in mice with conditional deletion of Pkd1. Here, we analyzed the effects of STA-2842 on liver size and cystic burden in Pkd-/- mice with established PLD. Using magnetic resonance imaging over time, we demonstrate that ten weeks of STA-2842 treatment significantly reduced both liver mass and cystic index suggesting selective elimination of cystic tissue. Pre-treatment cystic epithelia contain abundant HSP90; the degree of reduction in cysts was accompanied by inhibition of proliferation-associated signaling proteins EGFR and others, and induced cleavage of caspase 8 and PARP1, and correlated with degree of HSP90 inhibition and with inactivation of ERK1/2. Our results suggest that HSP90 inhibition is worth further evaluation as a therapeutic approach for patients with PLD.
authors.affiliation: Yale University, New Haven, Connecticut, 06520, United States of America; Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania, 19111, United States of America.
authors.forename: Zachary B
authors.initials: ZB
authors.lastname: Smithline
authors.affiliation: Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania, 19111, United States of America.
authors.forename: Anna S
authors.initials: AS
authors.lastname: Nikonova
authors.affiliation: Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania, 19111, United States of America.
authors.forename: Harvey H
authors.initials: HH
authors.lastname: Hensley
authors.affiliation: Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania, 19111, United States of America.
authors.forename: Kathy Q
authors.initials: KQ
authors.lastname: Cai
authors.affiliation: Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania, 19111, United States of America.
authors.forename: Brian L
authors.initials: BL
authors.lastname: Egleston
authors.affiliation: Synta Pharmaceuticals, Lexington, Massachusetts, 02421, United States of America.
authors.forename: David A
authors.initials: DA
authors.lastname: Proia
authors.affiliation: Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania, 19111, United States of America; Department I of Internal Medicine, Center for Integrated Oncology, University Hospital of Cologne, Cologne, 50937, Germany.
authors.forename: Tamina
authors.initials: T
authors.lastname: Seeger-Nukpezah
authors.affiliation: Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania, 19111, United States of America.
authors.forename: Erica A
authors.initials: EA
authors.lastname: Golemis
mesh_terms: D000818:Animals; D003560:Cysts / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D055786:Gene Knockout Techniques; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D018345:Mice, Knockout; D011493:Protein Kinase C / Q000235:genetics* / Q000378:metabolism; D012118:Resorcinols / Q000494:pharmacology* / Q000627:therapeutic use; D014230:Triazoles / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D018841:HSP90 Heat-Shock Proteins; D012118:Resorcinols; C000603842:STA-2842; D014230:Triazoles; C089212:protein kinase D; D011493:Protein Kinase C