title: MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells.
abstract: The discovery of cancer dependencies has the potential to inform therapeutic strategies and to identify putative drug targets. Integrating data from comprehensive genomic profiling of cancer cell lines and from functional characterization of cancer cell dependencies, we discovered that loss of the enzyme methylthioadenosine phosphorylase (MTAP) confers a selective dependence on protein arginine methyltransferase 5 (PRMT5) and its binding partner WDR77. MTAP is frequently lost due to its proximity to the commonly deleted tumor suppressor gene, CDKN2A. We observed increased intracellular concentrations of methylthioadenosine (MTA, the metabolite cleaved by MTAP) in cells harboring MTAP deletions. Furthermore, MTA specifically inhibited PRMT5 enzymatic activity. Administration of either MTA or a small-molecule PRMT5 inhibitor showed a modest preferential impairment of cell viability for MTAP-null cancer cell lines compared with isogenic MTAP-expressing counterparts. Together, our findings reveal PRMT5 as a potential vulnerability across multiple cancer lineages augmented by a common "passenger" genomic alteration.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Gregory V
authors.initials: GV
authors.lastname: Kryukov
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Frederick H
authors.initials: FH
authors.lastname: Wilson
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Ruth
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Joshiawa
authors.initials: J
authors.lastname: Paulk
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Aviad
authors.initials: A
authors.lastname: Tsherniak
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Sara E
authors.initials: SE
authors.lastname: Marlow
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Francisca
authors.initials: F
authors.lastname: Vazquez
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Weir
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Fitzgerald
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Minoru
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Craig M
authors.initials: CM
authors.lastname: Bielski
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Justin M
authors.initials: JM
authors.lastname: Scott
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Courtney
authors.initials: C
authors.lastname: Dennis
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Glenn S
authors.initials: GS
authors.lastname: Cowley
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Jesse S
authors.initials: JS
authors.lastname: Boehm
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Root
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Clary B
authors.initials: CB
authors.lastname: Clish
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. levi_garraway@dfci.harvard.edu.
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
mesh_terms: D045744:Cell Line, Tumor; D003839:Deoxyadenosines / Q000378:metabolism / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017353:Gene Deletion; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D011484:Protein-Arginine N-Methyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011683:Purine-Nucleoside Phosphorylase / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D013872:Thionucleosides / Q000378:metabolism / Q000494:pharmacology; D014157:Transcription Factors
chemical_list: D003839:Deoxyadenosines; D004791:Enzyme Inhibitors; C000599896:GSK3235025; D007546:Isoquinolines; D011743:Pyrimidines; D013872:Thionucleosides; D014157:Transcription Factors; C478359:WDR77 protein, human; C008500:5'-methylthioadenosine; C400529:PRMT5 protein, human; D011484:Protein-Arginine N-Methyltransferases; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase