PMID- 25436981
OWN - NLM
STAT- MEDLINE
DCOM- 20151109
LR  - 20231104
IS  - 1949-2553 (Electronic)
IS  - 1949-2553 (Linking)
VI  - 5
IP  - 24
DP  - 2014 Dec 30
TI  - Pre-clinical study of drug combinations that reduce breast cancer burden due to 
      aberrant mTOR and metabolism promoted by LKB1 loss.
PG  - 12738-52
AB  - Cancer therapies that simultaneously target activated mammalian target of 
      rapamycin (mTOR) and cell metabolism are urgently needed. The goal of our study 
      was to identify therapies that effectively inhibited both mTOR activity and 
      cancer cell metabolism in primary tumors in vivo. Using our mouse model of 
      spontaneous breast cancer promoted by loss of LKB1 expression in an ErbB2 
      activated model; referred to as LKB1-/-NIC mice, we evaluated the effect of novel 
      therapies in vivo on primary tumors. Treatment of LKB1-/-NIC mice with AZD8055 
      and 2-DG mono-therapies significantly reduced mammary gland tumorigenesis by 
      inhibiting mTOR pathways and glycolytic metabolism; however simultaneous 
      inhibition of these pathways with AZD8055/2-DG combination was significantly more 
      effective at reducing tumor volume and burden. At the molecular level, 
      combination treatment inhibited mTORC1/mTORC2 activity, selectively inhibited 
      mitochondria function and blocked MAPK pro-survival signaling responsible for the 
      ERK-p90RSK feedback loop. Our findings suggest that loss of LKB1 expression be 
      considered a marker for metabolic dysfunction given its role in regulating AMPK 
      and mTOR function. Finally, the outcome of our pre-clinical study confirms 
      therapies that simultaneously target mTORC1/mTORC2 and glycolytic metabolism in 
      cancer produce the best therapeutic outcome for the treatment of patients 
      harboring metabolically active HER2 positive breast cancers.
FAU - Andrade-Vieira, Rafaela
AU  - Andrade-Vieira R
AD  - Department of Biochemistry and Molecular Biology, Dalhousie University, Faculty 
      of Medicine, Halifax, Nova Scotia Canada.
FAU - Goguen, Donna
AU  - Goguen D
AD  - Department of Biochemistry and Molecular Biology, Dalhousie University, Faculty 
      of Medicine, Halifax, Nova Scotia Canada.
FAU - Bentley, Heidi A
AU  - Bentley HA
AD  - Department of Biochemistry and Molecular Biology, Dalhousie University, Faculty 
      of Medicine, Halifax, Nova Scotia Canada.
FAU - Bowen, Chris V
AU  - Bowen CV
AD  - Department of Radiology, Halifax, Nova Scotia Canada.
FAU - Marignani, Paola A
AU  - Marignani PA
AD  - Department of Biochemistry and Molecular Biology, Dalhousie University, Faculty 
      of Medicine, Halifax, Nova Scotia Canada.
LA  - eng
GR  - Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Oncotarget
JT  - Oncotarget
JID - 101532965
RN  - 0 (Imidazoles)
RN  - 0 (Morpholines)
RN  - 0 (Quinolines)
RN  - 970JJ37FPW 
      ((5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol)
RN  - 9G2MP84A8W (Deoxyglucose)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Stk11 protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - RUJ6Z9Y0DT (dactolisib)
SB  - IM
MH  - AMP-Activated Protein Kinases
MH  - Animals
MH  - Antineoplastic Combined Chemotherapy Protocols/*pharmacology
MH  - Deoxyglucose/administration & dosage/pharmacology
MH  - Disease Models, Animal
MH  - Female
MH  - Glycolysis/drug effects
MH  - Imidazoles/administration & dosage/pharmacology
MH  - Mammary Neoplasms, Experimental/*drug therapy/genetics/*metabolism/pathology
MH  - Mice
MH  - Mice, Transgenic
MH  - Molecular Targeted Therapy
MH  - Morpholines/administration & dosage/pharmacology
MH  - Protein Serine-Threonine Kinases/*deficiency/genetics/metabolism
MH  - Quinolines/administration & dosage/pharmacology
MH  - Signal Transduction
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/genetics/*metabolism
PMC - PMC4350354
EDAT- 2014/12/02 06:00
MHDA- 2015/11/10 06:00
PMCR- 2014/12/01
CRDT- 2014/12/02 06:00
PHST- 2014/10/20 00:00 [received]
PHST- 2014/11/24 00:00 [accepted]
PHST- 2014/12/02 06:00 [entrez]
PHST- 2014/12/02 06:00 [pubmed]
PHST- 2015/11/10 06:00 [medline]
PHST- 2014/12/01 00:00 [pmc-release]
AID - 2818 [pii]
AID - 10.18632/oncotarget.2818 [doi]
PST - ppublish
SO  - Oncotarget. 2014 Dec 30;5(24):12738-52. doi: 10.18632/oncotarget.2818.