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

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, Elliot S. Ballato, Eliot I. Behr, Ana C. deCarvalho, Roel G. W. Verhaak, John de Groot, Jason T. Huse, John M. Asara, Raghu Kalluri and Florian L. Muller ()
Additional contact information
Yasaman Barekatain: The University of Texas MD Anderson Cancer Center
Jeffrey J. Ackroyd: The University of Texas MD Anderson Cancer Center
Victoria C. Yan: The University of Texas MD Anderson Cancer Center
Sunada Khadka: The University of Texas MD Anderson Cancer Center
Lin Wang: Princeton University
Ko-Chien Chen: The University of Texas MD Anderson Cancer Center
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
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

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24240-3

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