title: Histone deacetylase activity mediates acquired resistance towards structurally diverse HSP90 inhibitors.
abstract: Heat shock protein 90 (HSP90) regulates multiple signalling pathways critical for tumour growth. As such, HSP90 inhibitors have been shown to act as effective anticancer agents in preclinical studies but, for a number of reasons, the same effect has not been observed in the clinical trials to date. One potential reason for this may be the presence of de novo or acquired resistance within the tumours. To investigate mechanisms of resistance, we generated resistant cell lines through gradual dose escalation of the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG). The resultant resistant cell lines maintained their respective levels of resistance (7-240×) in the absence of 17-AAG and were also cross-resistant with other benzoquinone ansamycin HSP90 inhibitors. Expression of members of the histone deacetylase family (HDAC 1, 5, 6) was altered in the resistant cells. To determine whether HDAC activity contributed to resistance, pan-HDAC inhibitors (TSA and LBH589) and the class II HDAC-specific inhibitor SNDX275 were found to resensitize resistant cells towards 17-AAG and 17-dimethylaminoethylamino-17-demethoxygeldanamycin. Most significantly, resistant cells were also identified as cross-resistant towards structurally distinct HSP90 inhibitors such as radicicol and the second-generation HSP90 inhibitors CCT018159, VER50589 and AUY922. HDAC inhibition also resensitized resistant cells towards these classes of HSP90 inhibitors. In conclusion, we report that prolonged 17-AAG treatment results in acquired resistance of cancer cells towards not just 17-AAG but also to a spectrum of structurally distinct HSP90 inhibitors. This acquired resistance can be inhibited using clinically relevant HDAC inhibitors. This work supports the potential benefit of using HSP90 and HDAC inhibitors in combination within the clinical setting.
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Clayton, Vic., Australia.|Bone Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Chai
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Clayton, Vic., Australia.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Vieusseux
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Clayton, Vic., Australia.|Department of Radiation Oncology, Centre for Life Sciences, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Lang
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Clayton, Vic., Australia.|College of Health and Biomedicine, Victoria University, Melbourne, Vic., Australia.
authors.forename: Chau H
authors.initials: CH
authors.lastname: Nguyen
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Clayton, Vic., Australia.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Kouspou
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Vic., Australia.|The Sir Peter MacCallum Department of Oncology, University of Melbourne, Vic., Australia.
authors.forename: Kara L
authors.initials: KL
authors.lastname: Britt
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Clayton, Vic., Australia.|College of Health and Biomedicine, Victoria University, Melbourne, Vic., Australia.|Australian Institute for Musculoskeletal Science (AIMSS), Victoria University and University of Melbourne, Vic., Australia.|Department of Medicine, Melbourne Medical School-Western Precinct, The University of Melbourne, St Albans, Vic., Australia.
authors.forename: John T
authors.identifier: 0000-0002-8244-1023
authors.initials: JT
authors.lastname: Price
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use*; D016227:Benzoquinones / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; D047029:Lactams, Macrocyclic; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; C112765:tanespimycin; D006655:Histone Deacetylases
keywords: 17-AAG; HSP90; acquired resistance; cancer; histone deacetylases