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, The Jackson Laboratory
John de Groot
Jason T Huse
John M Asara
Raghu Kalluri
Florian L Muller

This article is licensed under a Creative Commons Attribution 4.0 International License.


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.