title: MTAP Deletions in Cancer Create Vulnerability to Targeting of the MAT2A/PRMT5/RIOK1 Axis.
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.
authors.affiliation: Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Katya
authors.initials: K
authors.lastname: Marjon
authors.affiliation: Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Cameron
authors.affiliation: Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Phong
authors.initials: P
authors.lastname: Quang
authors.affiliation: Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Michelle F
authors.initials: MF
authors.lastname: Clasquin
authors.affiliation: Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Everton
authors.initials: E
authors.lastname: Mandley
authors.affiliation: Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Kaiko
authors.initials: K
authors.lastname: Kunii
authors.affiliation: Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: McVay
authors.affiliation: Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Sung
authors.initials: S
authors.lastname: Choe
authors.affiliation: Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Kernytsky
authors.affiliation: Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Gross
authors.affiliation: Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Zenon
authors.initials: Z
authors.lastname: Konteatis
authors.affiliation: Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Murtie
authors.affiliation: Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Blake
authors.affiliation: Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Travins
authors.affiliation: Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Marion
authors.initials: M
authors.lastname: Dorsch
authors.affiliation: Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Biller
authors.affiliation: Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA 02139, USA. Electronic address: kevin.marks@agios.com.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Marks
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000378:metabolism*; D017353:Gene Deletion; D023281:Genomics; D045325:HCT116 Cells; D006801:Humans; D008716:Methionine Adenosyltransferase / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism; D009369:Neoplasms / Q000201:enzymology* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism*; D011683:Purine-Nucleoside Phosphorylase / Q000172:deficiency / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D013872:Thionucleosides / Q000378:metabolism*
chemical_list: D000951:Antigens, Neoplasm; D046912:Multiprotein Complexes; D034741:RNA, Small Interfering; D013872:Thionucleosides; C021714:2-methylthioadenosine; C400529:PRMT5 protein, human; D011484:Protein-Arginine N-Methyltransferases; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase; C527161:MAT2A protein, human; D008716:Methionine Adenosyltransferase; D017346:Protein Serine-Threonine Kinases; C469385:RIOK1 protein, human; D000241:Adenosine