Methylthioadenosine is Not Dramatically Elevated inMTAP-Homozygous Deleted Primary Glioblastomas

Abstract

In BriefThe co-deletion ofMTAPin theCDKN2Alocus is a frequent event in diverse cancers including glioblastoma. Recent publications report that significant accumulations of the MTAP substrate, methylthioadenosine (MTA), can sensitizeMTAP-deleted cancer cells to novel inhibitors of PRMT5 and MAT2A for targeted therapy against tumors with this particular genetic alteration. In this work, using comprehensive metabolomic profiling, we show that MTA is primarily secreted, resulting in exceedingly high levels of extracellular MTAin vitro. We further show that primary human glioblastoma tumors minimally accumulate MTAin vivo, which is likely explained by the metabolism of MTA byMTAP-competent stromal cells. Together, these data challenge whether the metabolic conditions required for therapies to exploit vulnerabilities associatedMTAPdeletions are present in primary human tumors, questioning their translational efficacy in the clinic.HighlightsMethylthioadenosine (MTA) is elevated inMTAP-deleted cancer cellsin vitro, which provides a selective vulnerability to PRMT5 and MAT2A inhibitorsAccumulation of MTA inMTAP-deleted cancer cells is predominately extracellular, suggesting active secretion of MTA.MTAP-deleted primary human glioblastoma tumors show minimal intratumoral elevations of MTA, which is likely explained by secretion and metabolism byMTAP-competent stromal cells.SUMMARYHomozygous deletion of theCDK2NAlocus frequently results in co-deletion of methylthioadenosine phosphorylase (MTAP) in many fatal cancers such as glioblastoma multiforme (GBM), resulting in elevations of the substrate metabolite, methylthioadenosine (MTA). To capitalize on such accumulations, therapeutic targeting of protein arginine methyltransferase 5 (PRMT5) and methionine adenosyl transferase (MAT2A) are ongoing. While extensively corroboratedin vitro, the clinical efficacy of these strategies ultimately relies on equally significant accumulations of MTA in human tumors. Here, we show thatin vitroaccumulation of MTA is a predominately extracellular phenomenon, indicating secretion of MTA fromMTAP-deleted cells. In primary human GBMs, we find that MTA levels are not significantly higher inMTAP-deleted compared toMTAP-intact tumors or normal brain tissue. Together, these findings highlight the metabolic discrepancies betweenin vitromodels and primary human tumors and should thus be carefully considered in the development of the precision therapies targetingMTAP-homozygous deleted GBM.