PMID- 30918329
OWN - NLM
STAT- MEDLINE
DCOM- 20191217
LR  - 20231104
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 38
IP  - 26
DP  - 2019 Jun
TI  - Identification and characterization of two novel oncogenic mTOR mutations.
PG  - 5211-5226
LID - 10.1038/s41388-019-0787-5 [doi]
AB  - Mammalian target of rapamycin (mTOR) signaling is often aberrantly activated, 
      particularly when genetically altered, in human cancers. mTOR inhibitors 
      targeting the activated mTOR signaling are highly promising anti-cancer drugs. 
      Knowing the activating genetic change in mTOR can help guide the use of mTOR 
      inhibitors for cancer treatment. This study was conducted to identify and 
      characterize novel oncogenic mTOR mutations that can potentially be therapeutic 
      targets in human cancer. We sequenced 30 exons of the mTOR gene in 12 thyroid 
      cancer cell lines, 3 melanoma cell lines, 20 anaplastic thyroid cancer (ATC) 
      tumors, and 23 melanoma tumors and functionally characterized the identified 
      novel mTOR mutations in vitro and in vivo. We identified a novel point mutation 
      A1256G in ATC cell line and G7076A in melanoma tumor in exon 9 and exon 51 of the 
      mTOR gene, respectively. Over-expression of the corresponding mTOR mutants H419R 
      and G2359E created through induced mutagenesis showed markedly elevated protein 
      kinase activities associated with the activation of mTOR/p70S6K signaling in 
      HEK293T cells. Stable expression of the two mTOR mutants in NIH3T3 cells strongly 
      activated the mTOR/p70S6K signaling pathway and induced morphologic 
      transformation, cell focus formation, anchorage-independent cell growth, and 
      invasion. Inoculation of these mutant-expressing cells in athymic nude mice 
      induced rapid tumor development, showing their driving oncogenicity. We also 
      demonstrated that transfection with the novel mutants conferred cells high 
      sensitivities to the mTOR inhibitor temsirolimus. We speculate that human cancers 
      harboring these mTOR mutations, such as ATC and melanoma, may be effectively 
      treated with inhibitors targeting mTOR.
FAU - Murugan, Avaniyapuram Kannan
AU  - Murugan AK
AD  - Laboratory for Cellular and Molecular Thyroid Research, Division of 
      Endocrinology, Diabetes and Metabolism, Department of Medicine, Sidney Kimmel 
      Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, 
      Baltimore, MD, 21287, USA.
FAU - Liu, Rengyun
AU  - Liu R
AUID- ORCID: 0000-0002-1408-2372
AD  - Laboratory for Cellular and Molecular Thyroid Research, Division of 
      Endocrinology, Diabetes and Metabolism, Department of Medicine, Sidney Kimmel 
      Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, 
      Baltimore, MD, 21287, USA.
FAU - Xing, Mingzhao
AU  - Xing M
AD  - Laboratory for Cellular and Molecular Thyroid Research, Division of 
      Endocrinology, Diabetes and Metabolism, Department of Medicine, Sidney Kimmel 
      Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, 
      Baltimore, MD, 21287, USA. mxing1@jhmi.edu.
LA  - eng
GR  - R01 CA215142/CA/NCI NIH HHS/United States
GR  - R01 CA134225/CA/NCI NIH HHS/United States
GR  - R01 CA189224/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20190327
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Base Sequence
MH  - Carcinogenesis/*genetics
MH  - Cell Line, Tumor
MH  - DNA Mutational Analysis
MH  - Female
MH  - HEK293 Cells
MH  - Humans
MH  - Mice
MH  - Mice, Nude
MH  - Mice, Transgenic
MH  - Models, Molecular
MH  - *Mutation, Missense
MH  - NIH 3T3 Cells
MH  - TOR Serine-Threonine Kinases/chemistry/*genetics
PMC - PMC6597304
MID - NIHMS1523525
COIS- Declaration of interest The authors have no conflict of interest to declare.
EDAT- 2019/03/29 06:00
MHDA- 2019/12/18 06:00
PMCR- 2019/09/27
CRDT- 2019/03/29 06:00
PHST- 2018/09/21 00:00 [received]
PHST- 2019/03/07 00:00 [accepted]
PHST- 2019/02/12 00:00 [revised]
PHST- 2019/03/29 06:00 [pubmed]
PHST- 2019/12/18 06:00 [medline]
PHST- 2019/03/29 06:00 [entrez]
PHST- 2019/09/27 00:00 [pmc-release]
AID - 10.1038/s41388-019-0787-5 [pii]
AID - 10.1038/s41388-019-0787-5 [doi]
PST - ppublish
SO  - Oncogene. 2019 Jun;38(26):5211-5226. doi: 10.1038/s41388-019-0787-5. Epub 2019 
      Mar 27.