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
  • 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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