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Updated: May 20, 2026

A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
07:25

A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer

Published on: March 6, 2018

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

Nicolas Floc'h1, Carolyn Waugh Kinkade, Takashi Kobayashi

  • 1Department of Urology and Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10031, USA.

Cancer Research
|July 21, 2012
PubMed

Insights

Dual targeting of Akt and mTOR pathways with MK-2206 and ridaforolimus effectively inhibits castration-resistant prostate cancer (CRPC) in preclinical models. This combination therapy shows promise where single agents are less effective.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Castration-resistant prostate cancer (CRPC) remains a fatal disease with no curative treatments.
  • Targeting deregulated signaling pathways is a key strategy for CRPC therapy.

Purpose of the Study:

  • To investigate a novel therapeutic approach for CRPC by simultaneously targeting the Akt and mTOR signaling pathways.
  • To evaluate the efficacy of combined MK-2206 and ridaforolimus (MK-8669) in preclinical CRPC models.

Main Methods:

  • Utilized a refined genetically engineered mouse model for in vivo studies of CRPC.
  • Administered dual inhibitors MK-2206 (Akt inhibitor) and ridaforolimus (MK-8669, mTOR inhibitor).
  • Assessed drug effects on tumor phenotype, cellular proliferation (retinoblastoma pathway), and signaling pathway feedback in cell lines and mouse models.

Main Results:

  • Combination therapy with MK-2206 and ridaforolimus demonstrated high efficacy in inhibiting CRPC in vivo.
  • Single-agent treatment with MK-2206 or MK-8669 showed only modest effects on tumor phenotype.
  • Synergistic effects in human cell lines were partly attributed to limiting mTORC2 feedback activation of Akt, with effects mediated by retinoblastoma (Rb) pathway inhibition.

Conclusions:

  • Dual targeting of Akt and mTOR signaling pathways with MK-2206 and ridaforolimus presents a promising therapeutic strategy for CRPC.
  • This combination therapy may be particularly beneficial for CRPC patients with deregulated Rb pathway activity.

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