Efficacy of an HSP90 inhibitor, ganetespib, in preclinical thyroid cancer models

Shu Fu Lin*, Jen Der Lin, Chuen Hsueh, Ting Chao Chou, Chun Nan Yeh, Ming Huang Chen, Richard J. Wong

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

34 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)41294-41304
Number of pages11
JournalOncotarget
Volume8
Issue number25
DOIs
StatePublished - 2017

Bibliographical note

Publisher Copyright:
© Lin et al.

Keywords

  • Ganetespib
  • HSP90 inhibitor
  • Thyroid cancer

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