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Cancer Lett. 2017 Aug 1;400:110-116. doi: 10.1016/j.canlet.2017.04.019. Epub 2017 Apr 25.

The dual mTOR kinase inhibitor TAK228 inhibits tumorigenicity and enhances radiosensitization in diffuse intrinsic pontine glioma.

Author information

1
Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
2
Research Center for Genetic Medicine, Children's National Health System, Washington, District of Columbia 20010, USA.
3
Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
4
National Cancer Institute, National Institute of Health, Bethesda, MD 20892, USA.
5
Research Center for Genetic Medicine, Children's National Health System, Washington, District of Columbia 20010, USA; Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, District of Columbia 20052, USA.
6
Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: eraabe2@jhmi.edu.

Abstract

Diffuse intrinsic pontine glioma (DIPG) is an invasive and treatment-refractory pediatric brain tumor. Primary DIPG tumors harbor a number of mutations including alterations in PTEN, AKT, and PI3K and exhibit activation of mammalian Target of Rapamycin Complex 1 and 2 (mTORC1/2). mTORC1/2 regulate protein translation, cell growth, survival, invasion, and metabolism. Pharmacological inhibition of mTORC1 is minimally effective in DIPG. However, the activity of dual TORC kinase inhibitors has not been examined in this tumor type. Nanomolar levels of the mTORC1/2 inhibitor TAK228 reduced expression of p-AKTS473 and p-S6S240/244 and suppressed the growth of DIPG lines JHH-DIPG1, SF7761, and SU-DIPG-XIII. TAK228 induced apoptosis in DIPG cells and cooperated with radiation to further block proliferation and enhance apoptosis. TAK228 monotherapy inhibited the tumorigenicity of a murine orthotopic model of DIPG, more than doubling median survival (p = 0.0017) versus vehicle. We conclude that dual mTOR inhibition is a promising potential candidate for DIPG treatment.

KEYWORDS:

INK128; MLN0128; Pediatric brain tumor; Sapanisertib; mTOR

PMID:
28450157
PMCID:
PMC5569904
DOI:
10.1016/j.canlet.2017.04.019
[Indexed for MEDLINE]
Free PMC Article

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