PMID- 31841591
OWN - NLM
STAT- MEDLINE
DCOM- 20210427
LR  - 20211204
IS  - 1523-5866 (Electronic)
IS  - 1522-8517 (Print)
IS  - 1522-8517 (Linking)
VI  - 22
IP  - 4
DP  - 2020 Apr 15
TI  - Synergistic activity of mTORC1/2 kinase and MEK inhibitors suppresses pediatric 
      low-grade glioma tumorigenicity and vascularity.
PG  - 563-574
LID - 10.1093/neuonc/noz230 [doi]
AB  - BACKGROUND: Pediatric low-grade glioma (pLGG) is the most common childhood brain 
      tumor. Many patients with unresectable or recurrent/refractory tumors have 
      significant lifelong disability. The majority of pLGG have mutations increasing 
      the activity of the Ras/mitogen-activated protein kinase (MAPK) pathway. 
      Activation of mammalian target of rapamycin (mTOR) is also a hallmark of pLGG. We 
      therefore hypothesized that the dual target of rapamycin complexes 1 and 2 
      (TORC1/2) kinase inhibitor TAK228 would synergize with the mitogen-activated 
      extracellular signal-regulated kinase (MEK) inhibitor trametinib in pLGG. 
      METHODS: We tested TAK228 and trametinib in patient-derived pLGG cell lines 
      harboring drivers of pLGG including BRAFV600E and neurofibromatosis type 1 loss. 
      We measured cell proliferation, pathway inhibition, cell death, and senescence. 
      Synergy was analyzed via MTS assay using the Chou-Talalay method. In vivo, we 
      tested for overall survival and pathway inhibition and performed 
      immunohistochemistry for proliferation and vascularization. We performed a 
      scratch assay and measured angiogenesis protein activation in human umbilical 
      vein endothelial cells (HUVECs). RESULTS: TAK228 synergized with trametinib in 
      pLGG at clinically relevant doses in all tested cell lines, suppressing 
      proliferation, inducing apoptosis, and causing senescence in a cell 
      line-dependent manner. Combination treatment increased median survival by 70% and 
      reduced tumor volume compared with monotreatment and control cohorts. 
      Vascularization of tumors decreased as measured by CD31 and CD34. Combination 
      treatment blocked activation of focal adhesion kinase (FAK) and sarcoma 
      proto-oncogene non-receptor tyrosine kinase (SRC) in HUVEC cells and reduced 
      HUVEC migration compared with each drug alone. CONCLUSIONS: The combination of 
      TAK228 and trametinib synergized to suppress the growth of pLGG. These agents 
      synergized to reduce tumor vascularity and endothelial cell growth and migration 
      by blocking activation of FAK and SRC.
CI  - (c) The Author(s) 2019. Published by Oxford University Press on behalf of the 
      Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: 
      journals.permissions@oup.com.
FAU - Arnold, Antje
AU  - Arnold A
AD  - Johns Hopkins School of Medicine, Department of Pathology, Division of 
      Neuropathology, Baltimore, Maryland.
FAU - Yuan, Ming
AU  - Yuan M
AD  - Johns Hopkins School of Medicine, Department of Pathology, Division of 
      Neuropathology, Baltimore, Maryland.
FAU - Price, Antionette
AU  - Price A
AD  - Johns Hopkins School of Medicine, Department of Pathology, Division of 
      Neuropathology, Baltimore, Maryland.
FAU - Harris, Lauren
AU  - Harris L
AD  - Johns Hopkins University Krieger School of Arts and Sciences, Department of 
      Molecular and Cell Biology, Baltimore, Maryland.
FAU - Eberhart, Charles G
AU  - Eberhart CG
AD  - Johns Hopkins School of Medicine, Department of Pathology, Division of 
      Neuropathology, Baltimore, Maryland.
FAU - Raabe, Eric H
AU  - Raabe EH
AD  - Johns Hopkins School of Medicine, Department of Pathology, Division of 
      Neuropathology, Baltimore, Maryland.
AD  - Johns Hopkins School of Medicine, Sidney Kimmel Comprehensive Cancer Center, 
      Division of Pediatric Oncology, Baltimore, Maryland.
LA  - eng
GR  - P30 CA006973/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Neuro Oncol
JT  - Neuro-oncology
JID - 100887420
RN  - 0 (MAS1 protein, human)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Proto-Oncogene Mas)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
SB  - IM
CIN - Neuro Oncol. 2020 Sep 29;22(9):1404-1405. PMID: 32556220
MH  - Cell Line, Tumor
MH  - Cell Proliferation
MH  - Child
MH  - *Endothelial Cells
MH  - *Glioma/drug therapy
MH  - Humans
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mitogen-Activated Protein Kinase Kinases
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Proto-Oncogene Mas
PMC - PMC7158655
OTO - NOTNLM
OT  - INK 128
OT  - MLN0128
OT  - angiogenesis
OT  - sapanisertib
OT  - trametinib
EDAT- 2019/12/17 06:00
MHDA- 2021/04/28 06:00
PMCR- 2021/04/15
CRDT- 2019/12/17 06:00
PHST- 2019/12/17 06:00 [pubmed]
PHST- 2021/04/28 06:00 [medline]
PHST- 2019/12/17 06:00 [entrez]
PHST- 2021/04/15 00:00 [pmc-release]
AID - 5679447 [pii]
AID - noz230 [pii]
AID - 10.1093/neuonc/noz230 [doi]
PST - ppublish
SO  - Neuro Oncol. 2020 Apr 15;22(4):563-574. doi: 10.1093/neuonc/noz230.