Inhibition of Hsp90 augments docetaxel therapy in castrate resistant prostate cancer

Sheng Yu Ku, Elena Lasorsa, Remi Adelaiye, Swathi Ramakrishnan, Leigh Ellis, Roberto Pili

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

First line treatment of patients with castrate resistant prostate cancer (CRPC) primarily involves administration of docetaxel chemotherapy. Unfortunately, resistance to docetaxel therapy is an ultimate occurrence. Alterations in androgen receptor (AR) expression and signaling are associated mechanisms underlying resistance to docetaxel treatment in CRPC. Heat shock protein 90 (Hsp90) is a molecular chaperone, which regulates the activation, maturation and stability of critical signaling proteins involved in prostate cancer, including the AR. This knowledge and recent advances in compound design and development have highlighted Hsp90 as an attractive therapeutic target for the treatment of CRPC. We recently reported the development of a MYC-CaP castrate resistant (MYC-CaP/CR) transplant tumor model, which expresses amplified wild type AR. Within, we report that a second generation Hsp90 inhibitor, NVP-AUY922, inhibits cell growth and significantly induces cell death in MYC-CaP/CR and Pten-CaP/cE2 cell lines. NVP-AUY922 induced proteasome degradation of AR, though interestingly does not require loss of AR protein to inhibit AR transcriptional activity. Further, NVP-AUY922 increased docetaxel toxicity in MYC-CaP/CR and Pten-CaP/cE2 cell lines in vitro. Finally, NVP-AUY922/docetaxel combination therapy in mice bearing MYC-CaP/CR tumors resulted in greater anti-tumor activity compared to single treatment. This study demonstrates that NVP-AUY922 elicits potent activity towards AR signaling and augments chemotherapy response in a mouse model of CRPC, providing rationale for the continued clinical development of Hsp90 inhibitors in clinical trials for treatment of CRPC patients.

Original languageEnglish (US)
Article numbere103680
JournalPLoS One
Volume9
Issue number7
DOIs
StatePublished - Jul 29 2014
Externally publishedYes

Fingerprint

docetaxel
HSP90 Heat-Shock Proteins
Androgen Receptors
prostatic neoplasms
Prostatic Neoplasms
therapeutics
Tumors
Chemotherapy
Therapeutics
drug therapy
neoplasms
Bearings (structural)
Cells
cell lines
Transplants
molecular chaperones
Molecular Chaperones
Drug Therapy
Cell Line
Neoplasms

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Inhibition of Hsp90 augments docetaxel therapy in castrate resistant prostate cancer. / Ku, Sheng Yu; Lasorsa, Elena; Adelaiye, Remi; Ramakrishnan, Swathi; Ellis, Leigh; Pili, Roberto.

In: PLoS One, Vol. 9, No. 7, e103680, 29.07.2014.

Research output: Contribution to journalArticle

Ku, Sheng Yu ; Lasorsa, Elena ; Adelaiye, Remi ; Ramakrishnan, Swathi ; Ellis, Leigh ; Pili, Roberto. / Inhibition of Hsp90 augments docetaxel therapy in castrate resistant prostate cancer. In: PLoS One. 2014 ; Vol. 9, No. 7.
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