title: Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to dependence on PRMT5.
abstract: 5-Methylthioadenosine phosphorylase (MTAP) is a key enzyme in the methionine salvage pathway. The MTAP gene is frequently deleted in human cancers because of its chromosomal proximity to the tumor suppressor gene CDKN2A. By interrogating data from a large-scale short hairpin RNA-mediated screen across 390 cancer cell line models, we found that the viability of MTAP-deficient cancer cells is impaired by depletion of the protein arginine methyltransferase PRMT5. MTAP-deleted cells accumulate the metabolite methylthioadenosine (MTA), which we found to inhibit PRMT5 methyltransferase activity. Deletion of MTAP in MTAP-proficient cells rendered them sensitive to PRMT5 depletion. Conversely, reconstitution of MTAP in an MTAP-deficient cell line rescued PRMT5 dependence. Thus, MTA accumulation in MTAP-deleted cancers creates a hypomorphic PRMT5 state that is selectively sensitized toward further PRMT5 inhibition. Inhibitors of PRMT5 that leverage this dysregulated metabolic state merit further investigation as a potential therapy for MTAP/CDKN2A-deleted tumors.
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: Konstantinos J
authors.initials: KJ
authors.lastname: Mavrakis
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: E Robert
authors.initials: ER
authors.lastname: McDonald
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Schlabach
authors.affiliation: Novartis Institutes for Biomedical Research, Basel CH-4002, Switzerland.
authors.forename: Eric
authors.initials: E
authors.lastname: Billy
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Hoffman
authors.affiliation: Novartis Institutes for Biomedical Research, Basel CH-4002, Switzerland.
authors.forename: Antoine
authors.initials: A
authors.lastname: deWeck
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Ruddy
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: Kavitha
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authors.lastname: Venkatesan
authors.affiliation: Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Yu
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: Gregg
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authors.lastname: McAllister
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Stump
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: Rosalie
authors.initials: R
authors.lastname: deBeaumont
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Ho
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: Yingzi
authors.initials: Y
authors.lastname: Yue
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yan-Neale
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: Guizhi
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authors.lastname: Yang
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: Fallon
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authors.lastname: Lin
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Yin
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Gao
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: D Randal
authors.initials: DR
authors.lastname: Kipp
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: Songping
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: Joshua T
authors.initials: JT
authors.lastname: McNamara
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Sprague
authors.affiliation: Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Zheng
authors.affiliation: China Novartis Institutes for Biomedical Research, Shanghai 201203, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: Young Shin
authors.initials: YS
authors.lastname: Cho
authors.affiliation: China Novartis Institutes for Biomedical Research, Shanghai 201203, China.
authors.forename: Justin
authors.initials: J
authors.lastname: Gu
authors.affiliation: Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Crawford
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: David
authors.initials: D
authors.lastname: Ciccone
authors.affiliation: Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA.
authors.forename: Alberto C
authors.initials: AC
authors.lastname: Vitari
authors.affiliation: Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA.
authors.forename: Albert
authors.initials: A
authors.lastname: Lai
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Capka
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Hurov
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: Jeffery A
authors.initials: JA
authors.lastname: Porter
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: John
authors.initials: J
authors.lastname: Tallarico
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Mickanin
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: Emma
authors.initials: E
authors.lastname: Lees
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: Raymond
authors.initials: R
authors.lastname: Pagliarini
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Keen
authors.affiliation: Novartis Institutes for Biomedical Research, Basel CH-4002, Switzerland.
authors.forename: Tobias
authors.initials: T
authors.lastname: Schmelzle
authors.affiliation: Novartis Institutes for Biomedical Research, Basel CH-4002, Switzerland.
authors.forename: Francesco
authors.initials: F
authors.lastname: Hofmann
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA. william.sellers@novartis.com fstegmeier@ksqtx.com.
authors.forename: Frank
authors.initials: F
authors.lastname: Stegmeier
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA. william.sellers@novartis.com fstegmeier@ksqtx.com.
authors.forename: William R
authors.initials: WR
authors.lastname: Sellers
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D003839:Deoxyadenosines / Q000378:metabolism; D017353:Gene Deletion; D006801:Humans; D008715:Methionine / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D011683:Purine-Nucleoside Phosphorylase / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D013872:Thionucleosides / Q000378:metabolism
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D003839:Deoxyadenosines; D034741:RNA, Small Interfering; D013872:Thionucleosides; C008500:5'-methylthioadenosine; D008715:Methionine; C400529:PRMT5 protein, human; D011484:Protein-Arginine N-Methyltransferases; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase