PMID- 23085766
OWN - NLM
STAT- MEDLINE
DCOM- 20130611
LR  - 20220727
IS  - 1573-7217 (Electronic)
IS  - 0167-6806 (Linking)
VI  - 136
IP  - 3
DP  - 2012 Dec
TI  - Investigational drug MLN0128, a novel TORC1/2 inhibitor, demonstrates potent oral 
      antitumor activity in human breast cancer xenograft models.
PG  - 673-82
LID - 10.1007/s10549-012-2298-8 [doi]
AB  - Aberrant activation of the mammalian target of rapamycin (mTOR) signaling plays 
      an important role in breast cancer progression and represents a potential 
      therapeutic target for breast cancer. In this study, we report the impact of the 
      investigational drug MLN0128, a potent and selective small molecule active-site 
      TORC1/2 kinase inhibitor, on tumor growth and metastasis using human breast 
      cancer xenograft models. We assessed in vitro antiproliferative activity of 
      MLN0128 in a panel of breast cancer cell lines. We next evaluated the impact of 
      MLN0128 on tumor growth, angiogenesis and metastasis using mammary fat pad 
      xenograft models of a non-VEGF (ML20) and a VEGF-driven (MV165) MCF-7 sublines 
      harboring PIK3CA mutations. MLN0128 potently inhibited cell proliferation in 
      various breast cancer cell lines harboring PIK3CA (IC(50): 1.5-53 nM), PTEN 
      (IC(50): 1-149 nM), KRAS, and/or BRAF mutations (IC(50): 13-162 nM), and in human 
      endothelial cells (IC(50): 33-40 nM) in vitro. In vivo, MLN0128 decreased primary 
      tumor growth significantly in both non-VEGF (ML20; p = 0.05) and VEGF-driven 
      MCF-7 (MV165; p = 0.014) xenograft models. MLN0128 decreased the phosphorylation 
      of Akt, S6, 4E-BP1, and NDRG1 in both models. In contrast, rapamycin increased 
      Akt activity and failed to reduce the phosphorylation of 4E-BP1, PRAS40, and 
      NDRG1. VEGF-induced lung metastasis in MV165 is inhibited by MLN0128 and 
      rapamycin. In conclusion, MLN0128 inhibits TORC1/2-dependent signaling in 
      preclinical models of breast cancer. MLN0128 appears to be superior in blocking 
      mTORC1/2 signaling in contrast to rapamycin. Our findings support the clinical 
      research of MLN0128 in patients with breast cancer and metastasis.
FAU - Gokmen-Polar, Yesim
AU  - Gokmen-Polar Y
AD  - Department of Medicine, Indiana University School of Medicine, Walther Hall, 980 
      W Walnut Street, Building R3, Room C230, Indianapolis, IN 46202, USA. 
      ypolar@iupui.edu
FAU - Liu, Yi
AU  - Liu Y
FAU - Toroni, Rachel A
AU  - Toroni RA
FAU - Sanders, Kerry L
AU  - Sanders KL
FAU - Mehta, Rutika
AU  - Mehta R
FAU - Badve, Sunil
AU  - Badve S
FAU - Rommel, Christian
AU  - Rommel C
FAU - Sledge, George W Jr
AU  - Sledge GW Jr
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20121021
PL  - Netherlands
TA  - Breast Cancer Res Treat
JT  - Breast cancer research and treatment
JID - 8111104
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Benzoxazoles)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Proteins)
RN  - 0 (Pyrimidines)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.1.137 (PIK3CA protein, human)
RN  - EC 2.7.11.1 (BRAF protein, human)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins B-raf)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.1.3.67 (PTEN Phosphohydrolase)
RN  - EC 3.1.3.67 (PTEN protein, human)
RN  - JGH0DF1U03 (sapanisertib)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/blood/*pharmacology
MH  - Benzoxazoles/*pharmacology
MH  - Breast Neoplasms/*drug therapy/genetics/pathology
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Class I Phosphatidylinositol 3-Kinases
MH  - Endothelial Cells/drug effects/metabolism
MH  - Female
MH  - Humans
MH  - Lung Neoplasms/pathology/secondary
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mechanistic Target of Rapamycin Complex 2
MH  - Mice
MH  - Mice, Nude
MH  - Multiprotein Complexes/*antagonists & inhibitors/metabolism
MH  - Mutation
MH  - Neovascularization, Pathologic/drug therapy
MH  - PTEN Phosphohydrolase/genetics
MH  - Phosphatidylinositol 3-Kinases/genetics
MH  - Phosphorylation/drug effects
MH  - Protein Kinase Inhibitors/blood/*pharmacology
MH  - Proteins/*antagonists & inhibitors/metabolism
MH  - Proto-Oncogene Proteins B-raf/genetics
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Pyrimidines/*pharmacology
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism
MH  - Vascular Endothelial Growth Factor A/metabolism/pharmacology
MH  - Xenograft Model Antitumor Assays
EDAT- 2012/10/23 06:00
MHDA- 2013/06/12 06:00
CRDT- 2012/10/23 06:00
PHST- 2012/05/19 00:00 [received]
PHST- 2012/10/11 00:00 [accepted]
PHST- 2012/10/23 06:00 [entrez]
PHST- 2012/10/23 06:00 [pubmed]
PHST- 2013/06/12 06:00 [medline]
AID - 10.1007/s10549-012-2298-8 [doi]
PST - ppublish
SO  - Breast Cancer Res Treat. 2012 Dec;136(3):673-82. doi: 10.1007/s10549-012-2298-8. 
      Epub 2012 Oct 21.