the hsp90 inhibitor nvp-auy922 radiosensitizes by abrogation of homologous recombination resulting in mitotic entry with unresolved dna damage一半抑制剂nvp-auy922 radiosensitizes废除的同源重组导致有丝分裂条目未解决的dna损伤.pdf

The HSP90 Inhibitor NVP-AUY922 Radiosensitizes by Abrogation of Homologous Recombination Resulting in Mitotic Entry with Unresolved DNA Damage 1. 1 . 1 2 3 Shane Zaidi , Martin McLaughlin * , Shreerang A. Bhide , Suzanne A. Eccles , Paul Workman , 4 5 1,4 Christopher M. Nutting , Robert A. Huddart , Kevin J. Harrington 1Targeted Therapy Team, Institute of Cancer Research, Chester Beatty Laboratories, London, United Kingdom, 2 Tumour Biology and Metastasis Team, Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, Haddow Laboratories, Sutton, Surrey, United Kingdom, 3 Signal Transduction and Molecular Pharmacology Team, Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, Haddow Laboratories, Sutton, Surrey, United Kingdom, 4 The Royal Marsden Hospital, London, United Kingdom, 5 The Royal Marsden Hospital, Sutton, United Kingdom Abstract Background: Heat shock protein 90 (HSP90) is a molecular chaperone responsible for the conformational maintenance of a number of client proteins that play key roles in cell cycle arrest, DNA damage repair and apoptosis following radiation. HSP90 inhibitors exhibit antitumor activity by modulating the stabilisation and activation of HSP90 client proteins. We sought to evaluate NVP-AUY922, the most potent HSP90 inhibitor yet reported, in preclinical radiosensitization studies. Principal Findings: NVP-AUY922 potently radiosensitized cells in vitro at low nanomolar concentrations with a concurrent depletion of radioresistance-linked client proteins. Radiosensitization by NVP-AUY922 was verified for the first time