Open Access

Preclinical analysis of MTOR complex 1/2 inhibition in diffuse intrinsic pontine glioma

  • Authors:
    • Patrick C. Flannery
    • John A. DeSisto
    • Vladimir Amani
    • Sujatha Venkataraman
    • Rakeb T. Lemma
    • Eric W. Prince
    • Andrew Donson
    • Erin E. Moroze
    • Lindsey Hoffman
    • Jean M. Mulcahy Levy
    • Nicholas Foreman
    • Rajeev Vibhakar
    • Adam L. Green
  • View Affiliations

  • Published online on: November 29, 2017     https://doi.org/10.3892/or.2017.6122
  • Pages:455-464
  • Copyright: © Flannery et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Diffuse intrinsic pontine glioma (DIPG) is an incurable childhood brain tumor. The mechanistic target of rapamycin (MTOR), a key oncogene, functions as two distinct signaling complexes, MTORC1 and MTORC2. We set out to determine the preclinical efficacy and mechanism of action of MTOR inhibitors in DIPG. We evaluated the MTORC1 inhibitor everolimus and the MTORC1/2 inhibitor AZD2014 in three patient-derived DIPG cell lines using cell culture models. We created dose-response curves for both compounds. We measured phenotypic effects on cell self-renewal, apoptosis, cell cycle, differentiation, senescence, and autophagy. We assessed the effects of each compound on the AKT pathway. Finally, we measured the efficacy of AZD2014 in combination with radiation therapy (RT) and a panel of FDA-approved chemotherapy drugs. While everolimus showed minimal antitumor efficacy, AZD2014 revealed IC50 levels of 410-552 nM and IC90 levels of 1.30-8.86 µM in the three cell lines. AZD2014 demonstrated increased inhibition of cell self-renewal compared to everolimus. AZD2014 decreased expression of phospho-AKT, while no such effect was noted with everolimus. Direct AKT inhibition showed similar efficacy to AZD2014, and induction of constitutive AKT activity rescued DIPG cells from the effects of AZD2014. AZD2014 exhibited synergistic relationships with both RT and various chemotherapy agents across classes, including the multikinase inhibitor ponatinib. MTORC1/2 inhibition shows antitumor activity in cell culture models of DIPG due to the effect of MTORC2 inhibition on AKT. This strategy should be further assessed for potential incorporation into combinatorial approaches to the treatment of DIPG.

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February 2018
Volume 39 Issue 2

Print ISSN: 1021-335X
Online ISSN:1791-2431

2016 Impact Factor: 2.662
Ranked #31/217 Oncology
(total number of cites)

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APA
Flannery, P.C., DeSisto, J.A., Amani, V., Venkataraman, S., Lemma, R.T., Prince, E.W. ... Green, A.L. (2018). Preclinical analysis of MTOR complex 1/2 inhibition in diffuse intrinsic pontine glioma. Oncology Reports, 39, 455-464. https://doi.org/10.3892/or.2017.6122
MLA
Flannery, P. C., DeSisto, J. A., Amani, V., Venkataraman, S., Lemma, R. T., Prince, E. W., Donson, A., Moroze, E. E., Hoffman, L., Levy, J. M., Foreman, N., Vibhakar, R., Green, A. L."Preclinical analysis of MTOR complex 1/2 inhibition in diffuse intrinsic pontine glioma". Oncology Reports 39.2 (2018): 455-464.
Chicago
Flannery, P. C., DeSisto, J. A., Amani, V., Venkataraman, S., Lemma, R. T., Prince, E. W., Donson, A., Moroze, E. E., Hoffman, L., Levy, J. M., Foreman, N., Vibhakar, R., Green, A. L."Preclinical analysis of MTOR complex 1/2 inhibition in diffuse intrinsic pontine glioma". Oncology Reports 39, no. 2 (2018): 455-464. https://doi.org/10.3892/or.2017.6122