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

Nicolas Floc'h, Carolyn Waugh Kinkade, Takashi Kobayashi, Alvaro Aytes, Celine Lefebvre, Antonina Mitrofanova, Robert Cardiff, Andrea Califano, Michael M. Shen, Cory Abate-Shen

Research output: Contribution to journalArticle

49 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)4483-4493
Number of pages11
JournalCancer Research
Volume72
Issue number17
DOIs
StatePublished - Sep 1 2012

Fingerprint

Castration
Prostatic Neoplasms
Retinoblastoma
Therapeutics
ridaforolimus
Cell Proliferation
Phenotype
Cell Line
MK 2206
Pharmaceutical Preparations
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Floc'h, N., Kinkade, C. W., Kobayashi, T., Aytes, A., Lefebvre, C., Mitrofanova, A., ... Abate-Shen, C. (2012). Dual targeting of the Akt/mTOR signaling pathway inhibits castration-resistant prostate cancer in a genetically engineered mouse model. Cancer Research, 72(17), 4483-4493. https://doi.org/10.1158/0008-5472.CAN-12-0283

Dual targeting of the Akt/mTOR signaling pathway inhibits castration-resistant prostate cancer in a genetically engineered mouse model. / Floc'h, Nicolas; Kinkade, Carolyn Waugh; Kobayashi, Takashi; Aytes, Alvaro; Lefebvre, Celine; Mitrofanova, Antonina; Cardiff, Robert; Califano, Andrea; Shen, Michael M.; Abate-Shen, Cory.

In: Cancer Research, Vol. 72, No. 17, 01.09.2012, p. 4483-4493.

Research output: Contribution to journalArticle

Floc'h, N, Kinkade, CW, Kobayashi, T, Aytes, A, Lefebvre, C, Mitrofanova, A, Cardiff, R, Califano, A, Shen, MM & Abate-Shen, C 2012, 'Dual targeting of the Akt/mTOR signaling pathway inhibits castration-resistant prostate cancer in a genetically engineered mouse model', Cancer Research, vol. 72, no. 17, pp. 4483-4493. https://doi.org/10.1158/0008-5472.CAN-12-0283
Floc'h, Nicolas ; Kinkade, Carolyn Waugh ; Kobayashi, Takashi ; Aytes, Alvaro ; Lefebvre, Celine ; Mitrofanova, Antonina ; Cardiff, Robert ; Califano, Andrea ; Shen, Michael M. ; Abate-Shen, Cory. / Dual targeting of the Akt/mTOR signaling pathway inhibits castration-resistant prostate cancer in a genetically engineered mouse model. In: Cancer Research. 2012 ; Vol. 72, No. 17. pp. 4483-4493.
@article{4fa45573be3f4d7e8707fa8f13a792c6,
title = "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.",
author = "Nicolas Floc'h and Kinkade, {Carolyn Waugh} and Takashi Kobayashi and Alvaro Aytes and Celine Lefebvre and Antonina Mitrofanova and Robert Cardiff and Andrea Califano and Shen, {Michael M.} and Cory Abate-Shen",
year = "2012",
month = "9",
day = "1",
doi = "10.1158/0008-5472.CAN-12-0283",
language = "English (US)",
volume = "72",
pages = "4483--4493",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "17",

}

TY - JOUR

T1 - Dual targeting of the Akt/mTOR signaling pathway inhibits castration-resistant prostate cancer in a genetically engineered mouse model

AU - Floc'h, Nicolas

AU - Kinkade, Carolyn Waugh

AU - Kobayashi, Takashi

AU - Aytes, Alvaro

AU - Lefebvre, Celine

AU - Mitrofanova, Antonina

AU - Cardiff, Robert

AU - Califano, Andrea

AU - Shen, Michael M.

AU - Abate-Shen, Cory

PY - 2012/9/1

Y1 - 2012/9/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84865739094&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84865739094&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-12-0283

DO - 10.1158/0008-5472.CAN-12-0283

M3 - Article

C2 - 22815528

AN - SCOPUS:84865739094

VL - 72

SP - 4483

EP - 4493

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 17

ER -