JGM, Antineoplastic Agents, Brain, Brain Neoplasms, Cell Line, Tumor, Culture Media, Conditioned, Deoxyadenosines, Female, Frozen Sections, Glioblastoma, Homozygote, Humans, Metabolomics, Methionine Adenosyltransferase, Molecular Targeted Therapy, Precision Medicine, Protein-Arginine N-Methyltransferases, Purine-Nucleoside Phosphorylase, Sequence Deletion, Thionucleosides, Xenograft Model Antitumor Assays
Nat Commun 2021 Jul 9; 12(1):4228
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.
Barekatain, Yasaman; Ackroyd, Jeffrey J; Yan, Victoria C; Khadka, Sunada; Wang, Lin; Chen, Ko-Chien; Poral, Anton H; Tran, Theresa; Georgiou, Dimitra K; Arthur, Kenisha; Lin, Yu-Hsi; Satani, Nikunj; Ballato, Elliot S; Behr, Eliot I; deCarvalho, Ana C; Verhaak, Roel G W; de Groot, John; Huse, Jason T; Asara, John M; Kalluri, Raghu; and Muller, Florian L, "Homozygous MTAP deletion in primary human glioblastoma is not associated with elevation of methylthioadenosine." (2021). Faculty Research 2021. 148.