TORC1/2 kinase inhibition depletes glutathione and synergizes with carboplatin to suppress the growth of MYC-driven medulloblastoma

Rachael E Maynard; Brad Poore; Allison R Hanaford; Khoa Pham; Madison James; Jesse Alt; Youngran Park; Barbara S Slusher; Pablo Tamayo; Jill Mesirov; Tenley C Archer; Scott L Pomeroy; Charles G Eberhart; Eric H Raabe

doi:10.1016/j.canlet.2021.02.001

TORC1/2 kinase inhibition depletes glutathione and synergizes with carboplatin to suppress the growth of MYC-driven medulloblastoma

Cancer Lett. 2021 Apr 28:504:137-145. doi: 10.1016/j.canlet.2021.02.001. Epub 2021 Feb 8.

Authors

Affiliations

¹ Division of Pediatric Oncology, Department of Oncology, USA.
² Division of Pediatric Oncology, Department of Oncology, USA; Pathobiology Graduate Program, USA.
³ Division of Neuropathology, Department of Pathology, USA.
⁴ Pathobiology Graduate Program, USA.
⁵ Johns Hopkins Drug Discovery, USA.
⁶ Johns Hopkins Drug Discovery, USA; Department of Neurology, USA.
⁷ Moores Cancer Center, University of California San Diego, La Jolla, CA, USA; Center for Novel Therapeutics, University of California San Diego, La Jolla, CA, USA; Department of Medicine, University of California San Diego, La Jolla, CA, USA.
⁸ Moores Cancer Center, University of California San Diego, La Jolla, CA, USA; Department of Medicine, University of California San Diego, La Jolla, CA, USA.
⁹ Eli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Neurology, Boston Children's Hospital, Harvard Medical School, Cambridge, MA, USA.
¹⁰ Division of Neuropathology, Department of Pathology, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, USA.
¹¹ Division of Pediatric Oncology, Department of Oncology, USA; Division of Neuropathology, Department of Pathology, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, USA. Electronic address: eraabe2@jhmi.edu.

Abstract

Medulloblastoma is the most common malignant pediatric brain tumor. Tumors having high levels of c-MYC have the worst clinical prognosis, with only a minority of patients surviving. To address this unmet clinical need, we generated a human neural stem cell model of medulloblastoma that recapitulated the most aggressive subtype phenotypically and by mRNA expression profiling. An in silico analysis of these cells identified mTOR inhibitors as potential therapeutic agents. We hypothesized that the orally bioavailable TORC1/2 kinase inhibitor TAK228 would have activity against MYC-driven medulloblastoma. TAK228 inhibited mTORC1/2, decreased cell growth and caused apoptosis in high-MYC medulloblastoma cell lines. Comprehensive metabolic profiling of medulloblastoma orthotopic xenografts showed upregulation of glutathione compared to matched normal brain. TAK228 suppressed glutathione production. Because glutathione is required to detoxify platinum-containing chemotherapy, we hypothesized that TAK228 would cooperate with carboplatin in medulloblastoma. TAK228 synergized with carboplatin to inhibit cell growth and induce apoptosis and extended survival in orthotopic xenografts of high-MYC medulloblastoma. Brain-penetrant TORC1/2 inhibitors and carboplatin may be an effective combination therapy for high-risk medulloblastoma.

Keywords: Apoptosis; INK128; Pediatric brain tumor; Sapanisertib; mTOR.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use*
Carboplatin / therapeutic use*
Cell Proliferation / physiology*
Cerebellar Neoplasms / drug therapy
Cerebellar Neoplasms / enzymology
Cerebellar Neoplasms / metabolism
Cerebellar Neoplasms / pathology*
Female
Glutathione / metabolism*
Humans
Mechanistic Target of Rapamycin Complex 1 / antagonists & inhibitors*
Mechanistic Target of Rapamycin Complex 2 / antagonists & inhibitors*
Medulloblastoma / drug therapy
Medulloblastoma / enzymology
Medulloblastoma / metabolism
Medulloblastoma / pathology*
Mice
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use*
Proto-Oncogene Proteins c-myc / physiology*
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-myc
Carboplatin
Mechanistic Target of Rapamycin Complex 1
Mechanistic Target of Rapamycin Complex 2
Glutathione

Abstract

Publication types

MeSH terms

Substances

Grants and funding