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Homozygous MTAP deletion in primary human glioblastoma is not associated with elevation of methylthioadenosine

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  • Yasaman Barekatain

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center
    MD Anderson UT Health Graduate School of Biomedical Sciences)

  • Jeffrey J. Ackroyd

    (The University of Texas MD Anderson Cancer Center
    MD Anderson UT Health Graduate School of Biomedical Sciences)

  • Victoria C. Yan

    (The University of Texas MD Anderson Cancer Center
    MD Anderson UT Health Graduate School of Biomedical Sciences)

  • Sunada Khadka

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center
    MD Anderson UT Health Graduate School of Biomedical Sciences)

  • Lin Wang

    (Princeton University)

  • Ko-Chien Chen

    (The University of Texas MD Anderson Cancer Center
    MD Anderson UT Health Graduate School of Biomedical Sciences)

  • Anton H. Poral

    (The University of Texas MD Anderson Cancer Center)

  • Theresa Tran

    (The University of Texas MD Anderson Cancer Center)

  • Dimitra K. Georgiou

    (The University of Texas MD Anderson Cancer Center)

  • Kenisha Arthur

    (The University of Texas MD Anderson Cancer Center)

  • Yu-Hsi Lin

    (The University of Texas MD Anderson Cancer Center)

  • Nikunj Satani

    (The University of Texas MD Anderson Cancer Center)

  • Elliot S. Ballato

    (The University of Texas MD Anderson Cancer Center)

  • Eliot I. Behr

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Ana C. deCarvalho

    (Henry Ford Hospital)

  • Roel G. W. Verhaak

    (The Jackson Laboratory for Genomic Medicine)

  • John de Groot

    (The University of Texas MD Anderson Cancer Center)

  • Jason T. Huse

    (The University of Texas MD Anderson Cancer Center)

  • John M. Asara

    (Beth Israel Deaconess Medical Center)

  • Raghu Kalluri

    (The University of Texas MD Anderson Cancer Center)

  • Florian L. Muller

    (The University of Texas MD Anderson Cancer Center
    SPOROS Bioventures)

Abstract

Homozygous deletion of methylthioadenosine phosphorylase (MTAP) in cancers such as glioblastoma represents a potentially targetable vulnerability. Homozygous MTAP-deleted cell lines in culture show elevation of MTAP’s substrate metabolite, methylthioadenosine (MTA). High levels of MTA inhibit protein arginine methyltransferase 5 (PRMT5), which sensitizes MTAP-deleted cells to PRMT5 and methionine adenosyltransferase 2A (MAT2A) inhibition. While this concept has been extensively corroborated in vitro, the clinical relevance relies on exhibiting significant MTA accumulation in human glioblastoma. In this work, using comprehensive metabolomic profiling, we show that MTA secreted by MTAP-deleted cells in vitro results in high levels of extracellular MTA. We further demonstrate that homozygous MTAP-deleted primary glioblastoma tumors do not significantly accumulate MTA in vivo due to metabolism of MTA by MTAP-expressing stroma. These findings highlight metabolic discrepancies between in vitro models and primary human tumors that must be considered when developing strategies for precision therapies targeting glioblastoma with homozygous MTAP deletion.

Suggested Citation

  • Yasaman Barekatain & Jeffrey J. Ackroyd & Victoria C. Yan & Sunada Khadka & Lin Wang & Ko-Chien Chen & Anton H. Poral & Theresa Tran & Dimitra K. Georgiou & Kenisha Arthur & Yu-Hsi Lin & Nikunj Satani, 2021. "Homozygous MTAP deletion in primary human glioblastoma is not associated with elevation of methylthioadenosine," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24240-3
    DOI: 10.1038/s41467-021-24240-3
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    Cited by:

    1. Mrinal Gounder & Melissa Johnson & Rebecca S. Heist & Geoffrey I. Shapiro & Sophie Postel-Vinay & Frederick H. Wilson & Elena Garralda & Gerburg Wulf & Caroline Almon & Salah Nabhan & Elia Aguado-Frai, 2025. "MAT2A inhibitor AG-270/S095033 in patients with advanced malignancies: a phase I trial," Nature Communications, Nature, vol. 16(1), pages 1-11, December.

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