Targeting the mTOR Complex by Everolimus in NRAS Mutant Neuroblastoma

PloS One
Michael K KiesslingGerhard Rogler

Abstract

High-risk neuroblastoma remains lethal in about 50% of patients despite multimodal treatment. Recent attempts to identify molecular targets for specific therapies have shown that Neuroblastoma RAS (NRAS) is significantly mutated in a small number of patients. However, few inhibitors for the potential treatment for NRAS mutant neuroblastoma have been investigated so far. In this in-vitro study, we show that MEK inhibitors AZD6244, MEK162 and PD0325901 block cell growth in NRAS mutant neuroblastoma cell lines but not in NRAS wild-type cell lines. Several studies show that mutant NRAS leads to PI3K pathway activation and combined inhibitors of PI3K/mTOR effectively block cell growth. However, we observed the combination of MEK inhibitors with PI3K or AKT inhibitors did not show synergestic effects on cell growth. Thus, we tested single mTOR inhibitors Everolimus and AZD8055. Interestingly, Everolimus and AZD8055 alone were sufficient to block cell growth in NRAS mutant cell lines but not in wild-type cell lines. We found that Everolimus alone induced apoptosis in NRAS mutant neuroblastoma. Furthermore, the combination of mTOR and MEK inhibitors resulted in synergistic growth inhibition. Taken together, our results show that NRAS m...Continue Reading

References

Oct 20, 2007·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Maryam FouladiWayne L Furman
Jan 29, 2008·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Bret B Friday, Alex A Adjei
Jun 19, 2010·The New England Journal of Medicine·John M Maris
Jun 7, 2011·The New England Journal of Medicine·Paul B ChapmanUNKNOWN BRIM-3 Study Group
Oct 14, 2011·Nature Reviews. Cancer·Yuliya Pylayeva-GuptaDafna Bar-Sagi
Jul 24, 2012·Cell·Eran HodisLynda Chin
Jan 22, 2013·Nature Genetics·Trevor J PughJohn M Maris
Feb 23, 2013·Proceedings of the National Academy of Sciences of the United States of America·Christian PoschSusana Ortiz-Urda
Feb 28, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Federica CatalanottiPaul B Chapman
Mar 22, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Kadoaki OhashiWilliam Pao
Oct 18, 2014·Nature Reviews. Drug Discovery·Adrienne D CoxChanning J Der
Nov 12, 2014·Annual Review of Medicine·Chrystal U Louis, Jason M Shohet
Jun 30, 2015·Nature Genetics·Thomas F EleveldJohn M Maris

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Citations

Sep 11, 2016·BMC Genomics·Michael K KiesslingGuglielmo Roma
Nov 9, 2016·Critical Reviews in Oncology/hematology·Roberto LukschGian Paolo Tonini
Apr 13, 2017·Endocrine-related Cancer·Anna AngelousiAshley Grossman
Jan 21, 2017·PloS One·Michael K KiesslingGerhard Rogler
Apr 11, 2018·Nature Reviews. Cancer·Jamie I FletcherMurray D Norris
Mar 9, 2019·Journal of Cell Communication and Signaling·Dorota Ciołczyk-WierzbickaPiotr Laidler
Aug 11, 2018·American Journal of Physiology. Heart and Circulatory Physiology·Taylor A Johnson, Dinender K Singla
May 16, 2019·Experimental Hematology & Oncology·Tianyou YangYan Zou
May 28, 2019·International Journal of Hematology·Kanae SakakibaraKaoru Tohyama
Apr 23, 2017·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Birgit GeoergerSusan N Chi
Jun 8, 2021·Cancer Treatment Reviews·Tijana RandicStephanie Kreis
Nov 5, 2021·PLoS Computational Biology·Mathurin DorelNils Blüthgen

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Datasets Mentioned

BETA
MK2206

Methods Mentioned

BETA
GTPase
FCS
Transfection
reverse transcription-PCR
PCR
FACS
exome sequencing
Knock-down

Software Mentioned

CalcuSyn
GraphPad Prism
GraphPad Prims

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