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MAT2A Inhibition Blocks the Growth of MTAP-Deleted Cancer Cells by Reducing PRMT5-Dependent mRNA Splicing and Inducing DNA Damage.
Kalev, Peter; Hyer, Marc L; Gross, Stefan; Konteatis, Zenon; Chen, Chi-Chao; Fletcher, Mark; Lein, Max; Aguado-Fraile, Elia; Frank, Victoria; Barnett, Amelia; Mandley, Everton; Goldford, Joshua; Chen, Yue; Sellers, Katie; Hayes, Sebastian; Lizotte, Kate; Quang, Phong; Tuncay, Yesim; Clasquin, Michelle; Peters, Rachel; Weier, Jaclyn; Simone, Eric; Murtie, Joshua; Liu, Wei; Nagaraja, Raj; Dang, Lenny; Sui, Zhihua; Biller, Scott A; Travins, Jeremy; Marks, Kevin M; Marjon, Katya.
Afiliação
  • Kalev P; Biology, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
  • Hyer ML; Pharmacology, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
  • Gross S; Biochemistry and Biophysics, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
  • Konteatis Z; Chemistry, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
  • Chen CC; Bioinformatics, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
  • Fletcher M; Bioinformatics, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
  • Lein M; Drug Metabolism and Pharmacokinetics, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
  • Aguado-Fraile E; Clinical Biomarkers, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
  • Frank V; Biology, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
  • Barnett A; Biology, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
  • Mandley E; Pharmacology, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
  • Goldford J; Cell Metabolism, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
  • Chen Y; Drug Metabolism and Pharmacokinetics, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
  • Sellers K; Cell Metabolism, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
  • Hayes S; Cell Metabolism, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
  • Lizotte K; Cell Metabolism, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
  • Quang P; Biology, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
  • Tuncay Y; Biology, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
  • Clasquin M; Cell Metabolism, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
  • Peters R; Toxicology, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
  • Weier J; Biology, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
  • Simone E; Chemistry, Manufacturing and Control, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
  • Murtie J; Biology, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA; Pharmacology, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
  • Liu W; Bioinformatics, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
  • Nagaraja R; Drug Metabolism and Pharmacokinetics, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
  • Dang L; Biochemistry and Biophysics, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
  • Sui Z; Chemistry, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
  • Biller SA; Chemistry, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
  • Travins J; Chemistry, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
  • Marks KM; Biology, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
  • Marjon K; Biology, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA. Electronic address: katya.marjon@agios.com.
Cancer Cell ; 39(2): 209-224.e11, 2021 02 08.
Article em En | MEDLINE | ID: mdl-33450196
ABSTRACT
The methylthioadenosine phosphorylase (MTAP) gene is located adjacent to the cyclin-dependent kinase inhibitor 2A (CDKN2A) tumor-suppressor gene and is co-deleted with CDKN2A in approximately 15% of all cancers. This co-deletion leads to aggressive tumors with poor prognosis that lack effective, molecularly targeted therapies. The metabolic enzyme methionine adenosyltransferase 2α (MAT2A) was identified as a synthetic lethal target in MTAP-deleted cancers. We report the characterization of potent MAT2A inhibitors that substantially reduce levels of S-adenosylmethionine (SAM) and demonstrate antiproliferative activity in MTAP-deleted cancer cells and tumors. Using RNA sequencing and proteomics, we demonstrate that MAT2A inhibition is mechanistically linked to reduced protein arginine methyltransferase 5 (PRMT5) activity and splicing perturbations. We further show that DNA damage and mitotic defects ensue upon MAT2A inhibition in HCT116 MTAP-/- cells, providing a rationale for combining the MAT2A clinical candidate AG-270 with antimitotic taxanes.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteína-Arginina N-Metiltransferases / Dano ao DNA / RNA Mensageiro / Splicing de RNA / Purina-Núcleosídeo Fosforilase / Inibidores Enzimáticos / Metionina Adenosiltransferase Limite: Animals / Humans Idioma: En Revista: Cancer Cell Assunto da revista: NEOPLASIAS Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteína-Arginina N-Metiltransferases / Dano ao DNA / RNA Mensageiro / Splicing de RNA / Purina-Núcleosídeo Fosforilase / Inibidores Enzimáticos / Metionina Adenosiltransferase Limite: Animals / Humans Idioma: En Revista: Cancer Cell Assunto da revista: NEOPLASIAS Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos