Targeting glutaminolysis in chondrosarcoma in context of the IDH1/2 mutation

Br J Cancer. 2018 Apr;118(8):1074-1083. doi: 10.1038/s41416-018-0050-9. Epub 2018 Mar 26.

Abstract

Introduction: Chondrosarcoma is a malignant cartilage-forming bone tumour in which mutations in IDH1 and IDH2 frequently occur. Previous studies suggest an increased dependency on glutaminolysis in IDH1/2 mutant cells, which resulted in clinical trials with the drugs CB-839, metformin and chloroquine. In this study, the preclinical rationale for using these drugs as a treatment for chondrosarcoma was evaluated.

Methods: Expression of glutaminase was determined in 120 cartilage tumours by immunohistochemistry. Ten chondrosarcoma cell lines were treated with the metabolic compounds CB-849, metformin, phenformin (lipophilic analogue of metformin) and chloroquine.

Results: A difference in glutaminase expression levels between the different tumour grades (p = 0.001, one-way ANOVA) was identified, with the highest expression observed in high-grade chondrosarcomas. Treatment with CB-839, metformin, phenformin or chloroquine revealed that chondrosarcoma cell lines are sensitive to glutaminolysis inhibition. Metformin and phenformin decreased mTOR activity in chondrosarcoma cells, and metformin decreased LC3B-II levels, which is counteracted by chloroquine.

Conclusion: Targeting glutaminolysis with CB-839, metformin, phenformin or chloroquine is a potential therapeutic strategy for a subset of high-grade chondrosarcomas, irrespective of the presence or absence of an IDH1/2 mutation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / isolation & purification
  • Antineoplastic Agents / therapeutic use
  • Benzeneacetamides / therapeutic use*
  • Bone Neoplasms / drug therapy*
  • Bone Neoplasms / genetics
  • Bone Neoplasms / metabolism
  • Bone Neoplasms / pathology
  • Chloroquine / therapeutic use*
  • Chondrosarcoma / drug therapy*
  • Chondrosarcoma / genetics
  • Chondrosarcoma / metabolism
  • Chondrosarcoma / pathology
  • Drug Screening Assays, Antitumor
  • Glutaminase / antagonists & inhibitors
  • Glutaminase / metabolism*
  • Glutamine / metabolism*
  • Humans
  • Immunohistochemistry
  • Isocitrate Dehydrogenase / genetics
  • Metabolic Networks and Pathways / drug effects
  • Metformin / therapeutic use*
  • Molecular Targeted Therapy / methods
  • Mutation
  • Neoplasm Grading
  • Thiadiazoles / therapeutic use*
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Benzeneacetamides
  • CB-839
  • Thiadiazoles
  • Glutamine
  • Chloroquine
  • Metformin
  • IDH2 protein, human
  • Isocitrate Dehydrogenase
  • IDH1 protein, human
  • Glutaminase