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.

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