Synergistic activity of the mTOR inhibitor ridaforolimus and the antiandrogen bicalutamide in prostate cancer models

Int J Oncol. 2012 Aug;41(2):425-32. doi: 10.3892/ijo.2012.1487. Epub 2012 May 18.

Abstract

Although androgen ablation therapy is the foundation of current prostate cancer treatment, most patients ultimately develop castration-resistant disease. One proposed mechanism to account for androgen receptor (AR) activity in the castrate environment is via crosstalk with other signaling pathways. Specifically, reciprocal interactions between the AKT/mTOR and AR pathways have been implicated in prostate cancer progression. Here, we used the potent inhibitor ridaforolimus to target mTOR signaling alone and in combination with AR blockade by bicalutamide to examine the effect of abrogating these signaling pathways. Ridaforolimus treatment inhibited the proliferation of all six prostate cancer cell lines examined with the greatest sensitivity associated with loss of PTEN and elevated AKT/mTOR pathway activity. Dual inhibition of the AR and mTOR signaling pathways provided further benefit with the ridaforolimus-bicalutamide combination producing synergistic antiproliferative effects in prostate cancer cells in vitro when compared with each agent alone. Pharmacodynamic analysis confirmed that combination treatment resulted in full inhibition of each of the respective pathways. Importantly, the ridaforolimus-bicalutamide combination exhibited potent antitumor activity with parallel reductions in plasma PSA levels in vivo. Taken together, ridaforolimus exhibited potent antiproliferative and antitumor activity in prostate cancer models and the addition of bicalutamide represents a potentially effective combination strategy for patient therapy.

MeSH terms

  • Androgen Receptor Antagonists / administration & dosage
  • Anilides / administration & dosage
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Cell Cycle Checkpoints / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Synergism
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Nitriles / administration & dosage
  • PTEN Phosphohydrolase / metabolism
  • Prostate-Specific Antigen / blood
  • Prostate-Specific Antigen / metabolism
  • Prostatic Neoplasms / blood
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / pathology
  • Receptors, Androgen / metabolism
  • Signal Transduction / drug effects
  • Sirolimus / administration & dosage
  • Sirolimus / analogs & derivatives
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • Tosyl Compounds / administration & dosage
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Androgen Receptor Antagonists
  • Anilides
  • Nitriles
  • Receptors, Androgen
  • Tosyl Compounds
  • ridaforolimus
  • bicalutamide
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Prostate-Specific Antigen
  • Sirolimus