A novel HSP90 inhibitor with reduced hepatotoxicity synergizes with radiotherapy to induce apoptosis, abrogate clonogenic survival, and improve tumor control in models of colorectal cancer

// Linda Kinzel 1,* , Anne Ernst 1,* , Michael Orth 1,* , Valerie Albrecht 1 , Roman Hennel 1 , Nikko Brix 1 , Benjamin Frey 2 , Udo S. Gaipl 2 , Gabriele Zuchtriegel 3 , Christoph A. Reichel 3 , Andreas Blutke 4 , Daniela Schilling 5 , Gabriele Multhoff 5 , Minglun Li 1 , Maximilian Niyazi 1 , Anna A. Friedl 1 , Nicolas Winssinger 6 , Claus Belka 1 and Kirsten Lauber 1 1 Department of Radiation Oncology, Ludwig-Maximilians-University Munich, Munich, Germany 2 Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany 3 Department of Otorhinolaryngology, Head and Neck Surgery, and Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-University Munich, Munich, Germany 4 Institute of Veterinary Pathology at the Center for Clinical Veterinary Medicine, Ludwig-Maximilians-University Munich, Munich, Germany 5 Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany 6 Department of Organic Chemistry, NCCR Chemical Biology, University of Geneva, Geneva, Switzerland * These authors share equal first authorship Correspondence to: Kirsten Lauber, email: // Keywords : HSP90 inhibition, radiosensitization, colorectal cancer, DNA damage response, cell death Received : October 11, 2015 Accepted : May 24, 2016 Published : June 01, 2016 Abstract The chaperone heat shock protein 90 (HSP90) crucially supports the maturation, folding, and stability of a variety of client proteins which are of pivotal importance for the survival and proliferation of cancer cells. Consequently, targeting of HSP90 has emerged as an attractive strategy of anti-cancer therapy, and it appears to be particularly effective in the context of molecular sensitization towards radiotherapy as has been proven in preclinical models of different cancer entities. However, so far the clinical translation has largely been hampered by suboptimal pharmacological properties and serious hepatotoxicity of first- and second-generation HSP90 inhibitors. Here, we report on NW457, a novel radicicol-derived member of the pochoxime family with reduced hepatotoxicity, how it inhibits the DNA damage response and how it synergizes with ionizing irradiation to induce apoptosis, abrogate clonogenic survival, and improve tumor control in models of colorectal cancer in vitro and in vivo .