Dual targeting of the Akt/mTOR signaling pathway inhibits castration-resistant prostate cancer in a genetically engineered mouse model.

Abstract

Although the prognosis for clinically localized prostate cancer is now favorable, there are still no curative treatments for castration-resistant prostate cancer (CRPC) and, therefore, it remains fatal. In this study, we investigate a new therapeutic approach for treatment of CRPC, which involves dual targeting of a major signaling pathway that is frequently deregulated in the disease. We found that dual targeting of the Akt and mTOR signaling pathways with their respective inhibitors, MK-2206 and ridaforolimus (MK-8669), is highly effective for inhibiting CRPC in preclinical studies in vivo using a refined genetically engineered mouse model of the disease. The efficacy of the combination treatment contrasts with their limited efficacy as single agents, since delivery of MK-2206 or MK-8669 individually had a modest impact in vivo on the overall tumor phenotype. In human prostate cancer cell lines, although not in the mouse model, the synergistic actions of MK-2206 and ridaforolimus (MK-8669) are due in part to limiting the mTORC2 feedback activation of Akt. Moreover, the effects of these drugs are mediated by inhibition of cellular proliferation via the retinoblastoma (Rb) pathway. Our findings suggest that dual targeting of the Akt and mTOR signaling pathways using MK-2206 and ridaforolimus (MK-8669) may be effective for treatment of CRPC, particularly for patients with deregulated Rb pathway activity.

• Authors: Nicolas Floc'h, Carolyn Waugh Kinkade, Takashi Kobayashi, Alvaro Aytes, Celine Lefebvre, Antonina Mitrofanova, Robert D Cardiff, Andrea Califano, Michael M Shen, Cory Abate-Shen
• Journal: Cancer research (Cancer Res) Vol. 72 Issue 17 Pg. 4483-93 (Sep 01 2012) ISSN: 1538-7445 [Electronic] United States
• PMID: 22815528 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2012 AACR.

Chemical References

• Antineoplastic Agents
• Heterocyclic Compounds, 3-Ring
• MK 2206
• Retinoblastoma Protein
• ridaforolimus
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Sirolimus

Topics

• Animals
• Antineoplastic Agents (administration & dosage, pharmacology)
• Cell Line, Tumor
• Cluster Analysis
• Disease Models, Animal
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic (drug effects)
• Heterocyclic Compounds, 3-Ring (administration & dosage, pharmacology)
• Humans
• Male
• Mice
• Mice, Transgenic
• Orchiectomy
• Phenotype
• Prostatic Neoplasms (drug therapy, genetics, metabolism)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors)
• Retinoblastoma Protein (metabolism)
• Signal Transduction (drug effects)
• Sirolimus (administration & dosage, analogs & derivatives, pharmacology)
• TOR Serine-Threonine Kinases (antagonists & inhibitors)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays