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

Elisabeth F. P. Peterse, Bertine Niessen, Ruben D. Addie, Yvonne de Jong, Arjen H. G. Cleven, Alwine B. Kruisselbrink, Brendy E. W. M. van den Akker, Remco J. Molenaar, Anne-Marie Cleton-Jansen, Judith V. M. G. Bovée

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26 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)1074-1083
JournalBritish journal of cancer
Volume118
Issue number8
DOIs
Publication statusPublished - 2018

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