PMID- 22815528
OWN - NLM
STAT- MEDLINE
DCOM- 20121119
LR  - 20230404
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 72
IP  - 17
DP  - 2012 Sep 1
TI  - Dual targeting of the Akt/mTOR signaling pathway inhibits castration-resistant 
      prostate cancer in a genetically engineered mouse model.
PG  - 4483-93
LID - 10.1158/0008-5472.CAN-12-0283 [doi]
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.
CI  - (c)2012 AACR.
FAU - Floc'h, Nicolas
AU  - Floc'h N
AD  - Department of Urology and Pathology and Cell Biology, Columbia University Medical 
      Center, New York, NY 10031, USA.
FAU - Kinkade, Carolyn Waugh
AU  - Kinkade CW
FAU - Kobayashi, Takashi
AU  - Kobayashi T
FAU - Aytes, Alvaro
AU  - Aytes A
FAU - Lefebvre, Celine
AU  - Lefebvre C
FAU - Mitrofanova, Antonina
AU  - Mitrofanova A
FAU - Cardiff, Robert D
AU  - Cardiff RD
FAU - Califano, Andrea
AU  - Califano A
FAU - Shen, Michael M
AU  - Shen MM
FAU - Abate-Shen, Cory
AU  - Abate-Shen C
LA  - eng
GR  - U01 CA084294/CA/NCI NIH HHS/United States
GR  - U54CA121852/CA/NCI NIH HHS/United States
GR  - R01 CA173481/CA/NCI NIH HHS/United States
GR  - R01 CA115717/CA/NCI NIH HHS/United States
GR  - U01 CA105490/CA/NCI NIH HHS/United States
GR  - U54 CA121852/CA/NCI NIH HHS/United States
GR  - CA154293/CA/NCI NIH HHS/United States
GR  - R01 CA076501/CA/NCI NIH HHS/United States
GR  - CA084294/CA/NCI NIH HHS/United States
GR  - P01 CA154293/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120719
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Heterocyclic Compounds, 3-Ring)
RN  - 0 (MK 2206)
RN  - 0 (Retinoblastoma Protein)
RN  - 48Z35KB15K (ridaforolimus)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
EIN - Cancer Res. 2023 Apr 4;83(7):1160. PMID: 37014043
MH  - Animals
MH  - Antineoplastic Agents/administration & dosage/*pharmacology
MH  - Cell Line, Tumor
MH  - Cluster Analysis
MH  - Disease Models, Animal
MH  - Gene Expression Profiling
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Heterocyclic Compounds, 3-Ring/administration & dosage/*pharmacology
MH  - Humans
MH  - Male
MH  - Mice
MH  - Mice, Transgenic
MH  - Orchiectomy
MH  - Phenotype
MH  - Prostatic Neoplasms/drug therapy/genetics/*metabolism
MH  - Proto-Oncogene Proteins c-akt/*antagonists & inhibitors
MH  - Retinoblastoma Protein/metabolism
MH  - Signal Transduction/*drug effects
MH  - Sirolimus/administration & dosage/*analogs & derivatives/pharmacology
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
MH  - Tumor Burden/drug effects
MH  - Xenograft Model Antitumor Assays
PMC - PMC3432676
MID - NIHMS393840
EDAT- 2012/07/21 06:00
MHDA- 2012/12/10 06:00
PMCR- 2013/09/01
CRDT- 2012/07/21 06:00
PHST- 2012/07/21 06:00 [entrez]
PHST- 2012/07/21 06:00 [pubmed]
PHST- 2012/12/10 06:00 [medline]
PHST- 2013/09/01 00:00 [pmc-release]
AID - 0008-5472.CAN-12-0283 [pii]
AID - 10.1158/0008-5472.CAN-12-0283 [doi]
PST - ppublish
SO  - Cancer Res. 2012 Sep 1;72(17):4483-93. doi: 10.1158/0008-5472.CAN-12-0283. Epub 
      2012 Jul 19.