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Combination MEK and mTOR inhibitor therapy is active in models of glioblastoma.
Schreck, Karisa C; Allen, Amy N; Wang, Jiawan; Pratilas, Christine A.
Afiliação
  • Schreck KC; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA.
  • Allen AN; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
  • Wang J; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
  • Pratilas CA; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA.
Neurooncol Adv ; 2(1): vdaa138, 2020.
Article em En | MEDLINE | ID: mdl-33235998
BACKGROUND: RAS effector signaling pathways such as PI3K/mTOR and ERK are frequently dysregulated in glioblastoma. While small molecule targeted therapies against these pathways have appeared promising in preclinical studies, they have been disappointing in clinical trials due to toxicity and de novo and adaptive resistance. To identify predictors of glioblastoma sensitivity to dual pathway inhibition with mTORC1/2 and MEK inhibitors, we tested these agents, alone and in combination, in a cohort of genomically characterized glioblastoma cell lines. METHODS: Seven genomically characterized, patient-derived glioblastoma neurosphere cell lines were evaluated for their sensitivity to the dual mTORC1/2 kinase inhibitor sapanisertib (MLN0128, TAK-228) alone or in combination with the MEK1/2 inhibitor trametinib (GSK1120212), using assessment of proliferation and evaluation of the downstream signaling consequences of these inhibitors. RESULTS: Sapanisertib inhibited cell growth in neurosphere lines, but induced apoptosis only in a subset of lines, and did not completely inhibit downstream mTOR signaling via ribosomal protein S6 (RPS6). Growth sensitivity to MEK inhibitor monotherapy was observed in a subset of lines defined by loss of NF1, was predicted by an ERK-dependent expression signature, and was associated with effective phospho-RPS6 inhibition. In these lines, combined MEK/mTOR treatment further inhibited growth and induced apoptosis. Combined MEK and mTOR inhibition also led to modest antiproliferative effects in lines with intact NF1 and insensitivity to MEK inhibitor monotherapy. CONCLUSIONS: These data demonstrate that combined MEK/mTOR inhibition is synergistic in glioblastoma cell lines and may be more potent in NF1-deficient glioblastoma.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Prognostic_studies Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Prognostic_studies Idioma: En Ano de publicação: 2020 Tipo de documento: Article