2. Academic Validation
  3. The tyrphostin NT157 suppresses insulin receptor substrates and augments therapeutic response of prostate cancer

The tyrphostin NT157 suppresses insulin receptor substrates and augments therapeutic response of prostate cancer

  • Mol Cancer Ther. 2014 Dec;13(12):2827-39. doi: 10.1158/1535-7163.MCT-13-0842.
Naokazu Ibuki 1,  Mazyar Ghaffari 2,  Hadas Reuveni 3,  Mitali Pandey 4,  Ladan Fazli 4,  Haruhito Azuma 5,  Martin E Gleave 6,  Alexander Levitzki 7,  Michael E Cox 8
Affiliations

Affiliations

  • 1 The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada. Department of Urology, Osaka Medical College, Osaka, Japan.
  • 2 The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada. Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
  • 3 TyrNovo Ltd., Herzliya, Israel. Unit of Cellular Signaling, Department of Biological Chemistry, The Hebrew University of Jerusalem, Givat Ram, Jerusalem, Israel.
  • 4 The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada.
  • 5 Department of Urology, Osaka Medical College, Osaka, Japan.
  • 6 The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada. Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
  • 7 Unit of Cellular Signaling, Department of Biological Chemistry, The Hebrew University of Jerusalem, Givat Ram, Jerusalem, Israel.
  • 8 The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada. Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada. mcox@prostatecentre.com.
PMID: 25267499 DOI: 10.1158/1535-7163.MCT-13-0842
Abstract

Insulin-like growth factor (IGF) signaling is associated with castrate-resistant prostate Cancer (CRPC) progression. Insulin Receptor substrates 1 and 2 (IRS1/2) mediate mitogenic and antiapoptotic signaling from IGF1 receptor (IGF1R), Insulin Receptor, and other oncoproteins. This study demonstrates that IRS1/2 expression is increased in prostate Cancer, and persists in CRPC. Furthermore, this study assesses the Anticancer activity of NT157, a small molecule tyrphostin targeting IRS proteins, using androgen-responsive (LNCaP) and -independent (PC3) prostate Cancer cells in vitro and in vivo. NT157 treatment resulted in dose-dependent inhibition of IGF1R activation, suppression of IRS protein expression, inhibition of IGF1-induced Akt activation, but increased ERK activation in NT157-treated cells in vitro. These effects were correlated with decreased proliferation and increasing Apoptosis of LNCaP cells and increasing G2-M arrest in PC3 cells. NT157 also suppressed androgen-responsive growth, delayed CRPC progression of LNCaP xenografts, and suppressed PC3 tumor growth alone and in combination with docetaxel. This study reports the first preclinical proof-of-principle data that this novel small molecule tyrosine kinase inhibitor suppresses IRS1/2 expression, delays CRPC progression, and suppresses growth of CRPC tumors in vitro and in vivo. Demonstration that IRS expression can be increased in response to a variety of stressors that may lead to resistance or reduced effect of the therapies indicate that NT157-mediated IRS1/2 downregulation is a novel therapeutic approach for management of advanced prostate Cancer.

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