MTAP deletions in cancer create vulnerability to targeting of the MAT2A/PRMT5/RIOK1 axis

Marjon, Katya; Cameron, Michael J.; Quang, Phong; Clasquin, Michelle F.; Mandley, Everton; Kunii, Kaiko; McVay, Michael; Choe, Sung; Kernytsky, Andrew; Gross, Stefan; Konteatis, Zenon; Murtie, Joshua; Blake, Michelle L.; Travins, Jeremy; Dorsch, Marion; Biller, Scott A.; Marks, Kevin M.

doi:10.1016/j.celrep.2016.03.043

Cited by 499Cancer-related gene regulationRNA modifications and cancerBiochemical and Molecular Research

MTAP deletions in cancer create vulnerability to targeting of the MAT2A/PRMT5/RIOK1 axis

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Marjon, Katya, Cameron, Michael J., Quang, Phong, Clasquin, Michelle F., Mandley, Everton, Kunii, Kaiko, McVay, Michael, Choe, Sung +9 more·2016·Cell Reports

DOI 10.1016/j.celrep.2016.03.043

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Abstract

Homozygous deletions of p16/CDKN2A are prevalent in cancer, and these mutations commonly involve co-deletion of adjacent genes, including methylthioadenosine phosphorylase (MTAP). Here, we used shRNA screening and identified the metabolic enzyme, methionine adenosyltransferase II alpha (MAT2A), and the arginine methyltransferase, PRMT5, as vulnerable enzymes in cells with MTAP deletion. Metabolomic and biochemical studies revealed a mechanistic basis for this synthetic lethality. The MTAP substrate methylthioadenosine (MTA) accumulates upon MTAP loss. Biochemical profiling of a methyltransferase enzyme panel revealed that MTA is a potent and selective inhibitor of PRMT5. MTAP-deleted cells have reduced PRMT5 methylation activity and increased sensitivity to PRMT5 depletion. MAT2A produces the PRMT5 substrate S-adenosylmethionine (SAM), and MAT2A depletion reduces growth and PRMT5 methylation activity selectively in MTAP-deleted cells. Furthermore, this vulnerability extends to PRMT5 co-complex proteins such as RIOK1. Thus, the unique biochemical features of PRMT5 create an axis of targets vulnerable in CDKN2A/MTAP-deleted cancers.

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MTAP-null cancer cells are more sensitive to PRMT5 depletion than isogenic cancer cells that express MTAP.
“MTAP loss results in reduced PRMT5 activity and renders MTAP-null cancer cell more sensitive to PRMT5 depletion than isogenic counterparts that express MTAP (Kryukov et al., 2016; Marjon et al., 2016; Mavrakis et al., 2016).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Marjon et al., 2016
Loss of MTAP causes MTA to accumulate, and this MTA can inhibit PRMT5, creating a vulnerability in cancer cells.
“Loss of MTAP expression can result in another vulnerability for cancer cells because the MTA that accumulates following MTAP loss can act as a potent inhibitor of the enzyme arginine methyltransferase 5 (PRMT5).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Marjon et al., 2016
Ablating MAT2A reduces PRMT5-dependent methylation and proliferation in MTAP-deleted cancer cells.
“Additionally, ablation of methionine adenosyltransferase II alpha (MAT2A), the enzyme that produces the canonical and high-affinity PRMT5 substrate, S-adenosylmethionine (SAM), also reduces PRMT5-dependent methylation and proliferation in MTAP-deleted cancer cells (Marjon et al., 2016).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Marjon et al., 2016

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Abstract LB-307: MTAP deletions in cancer create vulnerability to a MAT2A/PRMT5/RIOK1 axis
Marks, K. M. (2016) · Cancer Research · doi:10.1158/1538-7445.am2016-lb-307
Self-citation
Abstract IA25: Targeting cancers with deletion of the p16/p14 tumor suppressor locus
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Self-citation
Abstract LB-017: Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to marked dependence on PRMT5
Mavrakis, K. J., McDonald, E. R., Schlabach, M. R., Billy, É., Hoffman, G. R., de Weck, A., Ruddy, D. A., Venkatesan, K., McAllister, G., deBeaumont, R. S., et al. (2016) · Cancer Research · doi:10.1158/1538-7445.am2016-lb-017 · Cited by 3 · see citing works
Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to dependence on PRMT5
Mavrakis, K. J., McDonald, E. R., Schlabach, M. R., Billy, E., Hoffman, G. R., deWeck, A., Ruddy, D. A., Venkatesan, K., Yu, J., McAllister, G., et al. (2016) · Science · doi:10.1126/science.aad5944 · Cited by 607 · see citing works

Authors: Marjon, K., Cameron, M. J., Quang, P., Clasquin, M. F., Mandley, E., Kunii, K., McVay, M., Choe, S., Kernytsky, A., Gross, S., Konteatis, Z., Murtie, J., Blake, M. L., Travins, J., Dorsch, M., Biller, S. A., & Marks, K. M.
Affiliations: Agios Pharmaceuticals (United States) (US)
Corresponding author: Marks, Kevin M.
ORCID: Clasquin, Michelle F.
Kunii, Kaiko
Choe, Sung
Konteatis, Zenon
Venue: Cell Reports
Publisher: Elsevier BV
Published: 2016-04
Volume: 15
Issue: 3
Pages: 574-587
ISSN: 2211-1247 (ISSN-L)
DOI: 10.1016/j.celrep.2016.03.043
OpenAlex: W2321587450
Cited by: 485
References: 50
Citations by year: 2026: 73 · 2025: 76 · 2024: 66 · 2023: 57 · 2022: 48 · 2021: 42 · 2020: 28 · 2019: 44 · 2018: 19 · 2017: 23 · 2016: 6
FWCI: 15.94
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by-nc-nd
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by-nc-nd/4.0/ (vor)
Locations: Cell Reports (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
Keywords: MTAP deletion, CDKN2A, synthetic lethality, PRMT5, MAT2A, RIOK1, methylthioadenosine, S-adenosylmethionine, arginine methylation, methionine metabolism, cancer vulnerability, shRNA screen
MeSH terms: Adenosine, Antigens, Neoplasm, Humans, Methionine Adenosyltransferase, Neoplasms, Protein-Arginine N-Methyltransferases, Purine-Nucleoside Phosphorylase, Thionucleosides, Signal Transduction, Protein Serine-Threonine Kinases, Gene Deletion, Genomics, RNA, Small Interfering, HCT116 Cells, Multiprotein Complexes

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MTAP deletions in cancer create vulnerability to targeting of the MAT2A/PRMT5/RIOK1 axis

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