TP53 mutated glioblastoma stem-like cell cultures are sensitive to dual mTORC1/2 inhibition while resistance in TP53 wild type cultures can be overcome by combined inhibition of mTORC1/2 and Bcl-2

Oncotarget. 2016 Sep 6;7(36):58435-58444. doi: 10.18632/oncotarget.11205.

Abstract

Background: Glioblastoma is the most malignant tumor of the central nervous system and still lacks effective treatment. This study explores mutational biomarkers of 11 drugs targeting either the RTK/Ras/PI3K, the p53 or the Rb pathway using 25 patient-derived glioblastoma stem-like cell cultures (GSCs).

Results: We found that TP53 mutated GSCs were approximately 3.5 fold more sensitive to dual inhibition of mammalian target of rapamycin complex 1 and 2 (mTORC1/2) compared to wild type GSCs. We identified that Bcl-2(Thr56/Ser70) phosphorylation contributed to the resistance of TP53 wild type GSCs against dual mTORC1/2 inhibition. The Bcl-2 inhibitor ABT-263 (navitoclax) increased sensitivity to the mTORC1/2 inhibitor AZD8055 in TP53 wild type GSCs, while sensitivity to AZD8055 in TP53 mutated GSCs remained unchanged.

Conclusion: Our data suggest that Bcl-2 confers resistance to mTORC1/2 inhibitors in TP53 wild type GSCs and that combined inhibition of both mTORC1/2 and Bcl-2 is worthwhile to explore further in TP53 wild type glioblastomas, whereas in TP53 mutated glioblastomas dual mTORC1/2 inhibitors should be explored.

Keywords: brain tumor; genetic biomarkers; personalized medicine; resistance; small molecule kinase inhibitors.

MeSH terms

  • Aniline Compounds / pharmacology
  • Biomarkers, Tumor
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / genetics*
  • Brain Neoplasms / metabolism
  • Cell Line, Tumor
  • Cell Survival
  • Cohort Studies
  • DNA Mutational Analysis
  • Drug Resistance, Neoplasm*
  • Drug Screening Assays, Antitumor
  • Glioblastoma / drug therapy
  • Glioblastoma / genetics*
  • Glioblastoma / metabolism
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Mechanistic Target of Rapamycin Complex 1 / antagonists & inhibitors*
  • Mechanistic Target of Rapamycin Complex 2 / antagonists & inhibitors*
  • Morpholines / chemistry
  • Mutation
  • Neoplastic Stem Cells / cytology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation
  • Proteome
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
  • Sulfonamides / pharmacology
  • TOR Serine-Threonine Kinases / metabolism
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Aniline Compounds
  • BCL2 protein, human
  • Biomarkers, Tumor
  • Morpholines
  • Proteome
  • Proto-Oncogene Proteins c-bcl-2
  • Sulfonamides
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • (5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol
  • MTOR protein, human
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • TOR Serine-Threonine Kinases
  • navitoclax