Efficacy of an HSP90 inhibitor, ganetespib, in preclinical thyroid cancer models
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Shu-Fu Lin1, Jen-Der Lin1, Chuen Hsueh2, Ting-Chao Chou3,7, Chun-Nan Yeh4, Ming-Huang Chen5 and Richard J. Wong6
1Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan
2Department of Pathology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
3Laboratory of Preclinical Pharmacology Core, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
4Department of Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan
5Department of Internal Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
6Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
7Current address: PD Science, Inc., Paramus, NJ, USA
Shu-Fu Lin, email: [email protected]
Keywords: HSP90 inhibitor, ganetespib, thyroid cancer
Received: October 29, 2016 Accepted: March 30, 2017 Published: April 18, 2017
Heat shock protein 90 is a molecular chaperon that maintains the correct folding and function of multiple client proteins. The inhibition of heat shock protein 90, which leads to the simultaneous degradation of multiple proteins involved in oncogenic signaling pathways, has revealed an innovative strategy to treat a variety of cancer types. We evaluated the therapeutic effects of ganetespib, a heat shock protein 90 inhibitor, in treating thyroid cancer. Ganetespib effectively inhibited cell proliferation in a dose-dependent manner in eight cell lines originating from four major histologic types of thyroid cancer (papillary, follicular, anaplastic and medullary). Ganetespib decreased cyclin-dependent kinase 1 and arrested cell cycle progression in G2/M phase. The expression of proteins involved in RAS/RAF/ERK and PI3K/AKT/mTOR signaling pathways was also inhibited. The RET level was decreased in a medullary thyroid cancer cell line. Ganetespib increased Bim expression, activated caspase-3 and induced apoptosis. In vivo, ganetespib retarded the tumor growth of anaplastic and medullary thyroid cancer xenografts with acceptable safety profiles. These findings indicate that ganetespib has potential in the treatment of patients with thyroid cancer.
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