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Title: mTORC1 upregulation via ERK-dependent gene expression change confers intrinsic resistance to MEK inhibitors in oncogenic KRas-mutant cancer cells.
Authors: Komatsu, Naoki
Fujita, Yoshihisa  kyouindb  KAKEN_id
Matsuda, Michiyuki  kyouindb  KAKEN_id  orcid https://orcid.org/0000-0002-5876-9969 (unconfirmed)
Aoki, Kazuhiro
Author's alias: 青木, 一洋
Issue Date: 5-Nov-2015
Publisher: Nature Publishing Group
Journal title: Oncogene
Volume: 34
Issue: 45
Start page: 5607
End page: 5616
Abstract: Cancer cells harboring oncogenic BRaf mutants, but not oncogenic KRas mutants, are sensitive to MEK inhibitors (MEKi). The mechanism underlying the intrinsic resistance to MEKi in KRas-mutant cells is under intensive investigation. Here, we pursued this mechanism by live imaging of extracellular signal-regulated kinases (ERK) and mammalian target of rapamycin complex 1 (mTORC1) activities in oncogenic KRas or BRaf-mutant cancer cells. We established eight cancer cell lines expressing Förster resonance energy transfer (FRET) biosensors for ERK activity and S6K activity, which was used as a surrogate marker for mTORC1 activity. Under increasing concentrations of MEKi, ERK activity correlated linearly with the cell growth rate in BRaf-mutant cancer cells, but not KRas-mutant cancer cells. The administration of PI3K inhibitors resulted in a linear correlation between ERK activity and cell growth rate in KRas-mutant cancer cells. Intriguingly, mTORC1 activity was correlated linearly with the cell growth rate in both BRaf-mutant cancer cells and KRas-mutant cancer cells. These observations suggested that mTORC1 activity had a pivotal role in cell growth and that the mTORC1 activity was maintained primarily by the ERK pathway in BRaf-mutant cancer cells and by both the ERK and PI3K pathways in KRas-mutant cancer cells. FRET imaging revealed that MEKi inhibited mTORC1 activity with slow kinetics, implying transcriptional control of mTORC1 activity by ERK. In agreement with this observation, MEKi induced the expression of negative regulators of mTORC1, including TSC1, TSC2 and Deptor, which occurred more significantly in BRaf-mutant cells than in KRas-mutant cells. These findings suggested that the suppression of mTORC1 activity and induction of negative regulators of mTORC1 in cancer cells treated for at least 1 day could be used as surrogate markers for the MEKi sensitivity of cancer cells.
Rights: This is the accepted manuscrip of the article is available at http://dx.doi.org/10.1038/onc.2015.16.
The full-text file will be made open to the public on 5 May 2016 in accordance with publisher's 'Terms and Conditions for Self-Archiving'.
この論文は出版社版でありません。引用の際には出版社版をご確認ご利用ください。This is not the published version. Please cite only the published version.
URI: http://hdl.handle.net/2433/207613
DOI(Published Version): 10.1038/onc.2015.16
PubMed ID: 25703330
Appears in Collections:Journal Articles

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