The potential and challenges of targeting MTAP-negative cancers beyond synthetic lethality
Author(s)
Bray, Chandler
Balcells, Cristina
Mcneish, Iain A
Keun, Hector C
Type
Journal Article
Abstract
Approximately 15% of cancers exhibit loss of the chromosomal locus 9p21.3 – the genomic location of the tumour suppressor gene CDKN2A and the methionine salvage gene methylthioadenosine phosphorylase (MTAP). A loss of MTAP increases the pool of its substrate methylthioadenosine (MTA), which binds to and inhibits activity of protein arginine methyltransferase 5 (PRMT5). PRMT5 utilises the universal methyl donor S-adenosylmethionine (SAM) to methylate arginine residues of protein substrates and regulate their activity, notably histones to regulate transcription. Recently, targeting PRMT5, or MAT2A that impacts PRMT5 activity by producing SAM, has shown promise as a therapeutic strategy in oncology, generating synthetic lethality in MTAP-negative cancers. However, clinical development of PRMT5 and MAT2A inhibitors has been challenging and highlights the need for further understanding of the downstream mediators of drug effects. Here, we discuss the rationale and methods for targeting the MAT2A/PRMT5 axis for cancer therapy. We evaluate the current limitations in our understanding of the mechanism of MAT2A/PRMT5 inhibitors and identify the challenges that must be addressed to maximise the potential of these drugs. In addition, we review the current literature defining downstream effectors of PRMT5 activity that could determine sensitivity to MAT2A/PRMT5 inhibition and therefore present a rationale for novel combination therapies that may not rely on synthetic lethality with MTAP loss.
Date Issued
2023-09-19
Date Acceptance
2023-09-04
Citation
Frontiers in Oncology, 2023, 13
ISSN
2234-943X
Publisher
Frontiers Media S.A.
Journal / Book Title
Frontiers in Oncology
Volume
13
Copyright Statement
Copyright © 2023 Bray, Balcells, McNeish and Keun. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
License URL
Identifier
https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2023.1264785/full
Subjects
ARGININE METHYLTRANSFERASE 5
COLON-CANCER
DETAINED INTRONS
IN-VIVO
Life Sciences & Biomedicine
MAT2A
MAT2A INHIBITOR
metabolism
methionine
METHIONINE ADENOSYLTRANSFERASE 2A
METHYLTHIOADENOSINE PHOSPHORYLASE-DEFICIENCY
MTAP
Oncology
PRE-MESSENGER-RNA
PRMT5
S-ADENOSYLMETHIONINE
Science & Technology
SELECTIVE INHIBITOR
synthetic lethality
Publication Status
Published
Article Number
1264785
Date Publish Online
2023-09-10