2. Academic Validation
  3. MAT2A Inhibition Blocks the Growth of MTAP-Deleted Cancer Cells by Reducing PRMT5-Dependent mRNA Splicing and Inducing DNA Damage

MAT2A Inhibition Blocks the Growth of MTAP-Deleted Cancer Cells by Reducing PRMT5-Dependent mRNA Splicing and Inducing DNA Damage

  • Cancer Cell. 2021 Feb 8;39(2):209-224.e11. doi: 10.1016/j.ccell.2020.12.010.
Peter Kalev 1,  Marc L Hyer 2,  Stefan Gross 3,  Zenon Konteatis 4,  Chi-Chao Chen 5,  Mark Fletcher 5,  Max Lein 6,  Elia Aguado-Fraile 7,  Victoria Frank 1,  Amelia Barnett 1,  Everton Mandley 2,  Joshua Goldford 8,  Yue Chen 6,  Katie Sellers 8,  Sebastian Hayes 8,  Kate Lizotte 8,  Phong Quang 1,  Yesim Tuncay 1,  Michelle Clasquin 8,  Rachel Peters 9,  Jaclyn Weier 1,  Eric Simone 10,  Joshua Murtie 11,  Wei Liu 5,  Raj Nagaraja 6,  Lenny Dang 3,  Zhihua Sui 4,  Scott A Biller 4,  Jeremy Travins 4,  Kevin M Marks 1,  Katya Marjon 12
Affiliations

Affiliations

  • 1 Biology, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
  • 2 Pharmacology, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
  • 3 Biochemistry and Biophysics, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
  • 4 Chemistry, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
  • 5 Bioinformatics, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
  • 6 Drug Metabolism and Pharmacokinetics, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
  • 7 Clinical Biomarkers, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
  • 8 Cell Metabolism, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
  • 9 Toxicology, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
  • 10 Chemistry, Manufacturing and Control, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
  • 11 Biology, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA; Pharmacology, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
  • 12 Biology, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA. Electronic address: [email protected].
PMID: 33450196 DOI: 10.1016/j.ccell.2020.12.010
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.

Keywords

DNA damage; Fanconi anemia complex; MAT2A; PRMT5; R loops; detained introns; splicing; synergy; taxanes.

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